合成6,7-Methylenedioxy-2-(2,3,4-substituted phenyl)-4-quinolone及其前驅物做為具抗癌潛能之抗癌藥; Synthesis of 6,7-Methylenedioxy-2-(2,3,4-substituted phenyl)-4-quinolone and their Prodrugs as potential anticancer agents

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(1)ύ୯ᙴᛰεᏢᛰᏢଣ ύ୯ᙴᛰεᏢᛰᏢଣ ᛰ‫ނ‬ϯᏢࣴ‫܌ز‬ᅺγፕЎ ᛰ‫ނ‬ϯᏢࣴ‫܌ز‬ᅺγፕЎ ࡰᏤ௲௤Ǻ ࡰᏤ௲௤Ǻ೾౰շ ௲. ௤. ஭ᇞ౺ շ౛௲௤. ӝԋ 6,7-Methylenedioxy-2-(2,3,4-substituted. phenyl)-4-quinolone Ϸ‫߻ځ‬០‫לڀࣁ଺ނ‬ᕎወૈϐ‫ל‬ ᕎᛰ. Synthesis of 6,7-Methylenedioxy-2-(2,3,4-substituted phenyl)-4-quinolone and their Prodrugs as potential anticancer agents. ࣴ‫ز‬ғǺ ࣴ‫ز‬ғǺणৎ଻. Fan, Chia-Wei. ύ. ๮. ҇. ୯. ΐ Μ Ϥ. ԃ. Ύ. Д.

(2) ᖴ. ᜏ. ҁፕЎ‫܍‬ᆾ཰ৣ೾౰շᖱ০௲௤ǵ໳‫ߏ܌‬᜽ብ௲௤аϷϷ ஭ᇞ౺շ౛௲௤ϐ਺ϪࡰᏤǴ٬ளа໩ճֹԋǴӧԜठ΢җ૱ ‫ޑ‬གᖴǶҭ‫ܭ‬ፕЎα၂ਔǴᆾ୯ٛᙴᏢεᏢ‫׵‬௲௤ӼᄪЬҺჹ ҁፕЎϐኘϧቩࢗǴඁᆶᝊ຦ཀ‫ـ‬ᆶࡰ҅Ǵ٬ҁፕЎளа‫׳‬ᑪ ֹ๓Ǵ໻Ԝལठന၈ኑϐᖴཀǶ ࣴ‫ز‬ය໔٠ᆾഋയඵ௲௤ǵ‫׵‬੦ᆄ௲௤ǵߋੀඁ௲௤ǵЦ ᝩѳ௲௤ǵ݅‫ے‬ѳୋ௲௤ǵֆᒸғୋ௲௤ǵೱߎࠤୋ௲௤ǵ໳ ໩ᕄշ౛௲௤Ϸ‫܌س‬ϣፏՏৣߏϐᜢᚶࡰᏤǴ‫੻ڙ‬ঘభǶҁፕ Ў‫܍‬ᆾ҉ᇻԃᇸ‫ޑ‬ᠭ‫ۆ‬-ᠭᇟችλ‫ۆ‬ϐӚ໨‫ڐ‬շϷഋ‫ފ‬։λ‫ۆ‬ жෳ፦᛼ǴӧԜठ΢ᖴཀǶ གᖴቅӬ੿λ‫ۆ‬ǵᒘဖᖚλ‫ۆ‬ǵ๮㗟ᏢߏǵϡྣᏢߏǵᅴ ࣦᏢ‫ۊ‬ǵҥธᏢߏǵࡿӝᏢߏǵࡌ‫׊‬Ꮲߏǵ႘‫܃‬Ꮲ‫ۊ‬ǵ໋ၲᏢ ߏǵች‫܃‬Ꮲ‫ۊ‬ǵ‫ޱ܃‬Ꮲ‫ۊ‬ǵӃએᏢߏǵ‫࣓܃‬Ꮲ‫ۊ‬ǵల࣓Ꮲ‫ۊ‬ǵ ᯧᦒᏢ‫ۊ‬ǵϘണᏢߏǵ࢙ۘᏢߏǵ‫ݒޚ‬Ꮲߏǵ჏ᑯᏢ‫ۊ‬ǵੀᓄ Ꮲ‫׌‬Ϸӕ੤ӕᏢܴቺǵལণǵгѶǵ࢙Ճǵߪܹǵ௴҇ǵ੦࣓ǵ ᆬϡ฻Γ‫ܭ‬ჴᡍϷғࢲ΢ϐᜢᚶǶԜѦǴ‫܌‬΢‫ޑ‬ε߻፸ߪϘᏢ ߏᆶऍ๮Ꮲ‫ۊ‬ǵϺϺऀ๱ࡐь೯‫ॳ܃ޑ‬Ꮲ‫ۊ‬ǵ໒ਟ‫ޑ‬ᙝᙝદዝ Ꮲ‫ۊ‬ǵঁ‫܄‬ӳ‫ޑ‬λ੤໡࣓Ꮲ‫ۊ‬ǵ౜ӧᗋངҔ໵қ࣬ᐒ‫ޑ‬٫࿡Ꮲ I.

(3) ‫ۂ‬ǵ‫ک‬ᝰёᒃ‫ࡏޑ‬ᆺᏢ‫ۂ‬ǵೀ٣༝ᑼ‫ޑ‬ഩ᜻Ꮲߏǵ‫܌‬΢‫ޑ‬ႝတ ᙴғࢅരᏢߏǵѦࠠమ౏‫ޑ‬ਕ‫ػ‬Ꮲߏǵᄺോᢌ+ჴᡍࡐઓ+Ԗ ጔ‫ ޑ‬Wasme γሳᏢߏǵჹΓғࡐԖೕჄ‫ޑ‬໳ߎൂ‫ي‬ᅇ‫ߪژژ‬ ᓪᏢߏǵԖ୼ߓಮΚ+ᒃϪ‫ࡿۑߓޑ‬ᆺᏢ‫ۊ‬ǵ‫ئ‬ང online+ࢲዃ ‫ޑ‬඲඲ᛏЎᏢ‫ۊ‬Ǵᖴᖴգॺම࿶๏‫ߎޑ‬ҏ‫قؼ‬ǴᗋԖ೚ӭჴᡍ Ϸғࢲ΢‫ޑ‬λѕᓲᆶᔅշǶ җ૱གᖴǴᆶ‫ך‬රδ࣬ೀ‫ޑ‬ઓ‫ڻ‬ᝊ‫ॺن‬Ǻࡇ਻ࢩྈ+዗Ј ᅈϩ+࡫ࠂΜ‫ޑى‬ᄣᄣӵ‫ޱ‬ǵ‫׷ي‬΋᏾ঁଯ౿+଺٣௃ᕴࢂಒ Ј೛གྷ‫ޑډڬ‬ፆ҆ѯ௵ǵ߁ङᅜဈ+ਔத௃က࣬ਇ‫ޑ‬ФФШ ‫ؼ‬ǵϺғђ෎+Ԗ΋ୋӳЈဉ‫࠶ޑ‬ԃǵऀ๱ਔۘԖࠠ+ঁ‫܄‬໒ ਟང዗Ꮅ‫ޑ‬λऍ੦ૠǵ‫਻و‬፦ၡጕ+໿‫ ڥ‬2 ೰፪‫ ޑ‬soso ‫ذ‬દǵ ٛᠴфϻᄇۭ+Вቃ஑ৎ‫ֻ܃ޑ‬ǵ഻Ծ high+‫ޕ‬᛽ᙦ൤‫ߓޑ‬Ѳ ণᆢǵ඀ផ΋௼+ന߈தத kuso ‫ߓޑ‬ᔾᄪᔾǵ഻ངࡨࡨ+ᇡ੿ ոΚ‫ޑ‬εқᅜഩோǴ೭٤ঁВη္Ǵၟգॺεұ࣬ೀӧ΋ଆࡐ ඍ‫ז‬Ǵ‫؂‬Ϻ೿Ԗಠόֹ‫ޑ‬፪٣Ǵচҁаࣁ࢏ᔿ‫ޑ‬ғࢲӢࣁԖΑ գॺᡂளӭߍӭ࠮Ǵ੿‫ޑ‬όᒘ^^Ǽ੝ձགᖴǺຬང toro ∇‫܃ޑ‬ ыӧα၂ය໔๏ϒፏӭᔅԆǵᕴࢂགྷଆ‫ך‬+๏‫ך‬Ⴔᓰޭ‫ޑۓ‬ε Ꮲӳ϶୯ຬᆶᆧᐇǵόਔ๏ϒᜢЈᆶЍ࡭‫ޑ‬٩޼ǵࣴ‫܌ز‬ၸٰ ΓӕਔΨࢂߙఘᙔЎ‫ۆ‬+Ԯଭຓ්л๏‫ߞޑ‬Јᆶࡌ᝼…ᗋԖࡐ II.

(4) ӭࡐӭܻ϶Ԗ‫׎‬ค‫ޑ׎‬ᔅԆᆶઔᅽǴ೿ᖴᖴգॺǶ Ў҃Ǵ‫ך‬གྷஒ೭ҽளٰόܰ‫ޑ‬ᄪᝬ᝘๏‫ך‬ኑང‫ޑ‬ৎΓǺӄ Шࣚനᠰৎǵ൤ԖೢҺགǵค࡜ค৷όीжሽჹৎΓбр‫ޑ‬Դ ϻ‫ ۀ‬-‫ݿݿ‬ण຾బӃғᆶ༰༰ቅ⃎ስζγǴӢࣁգॺ‫ޑ‬ᐟᓰǴ ‫ך‬ωૈ߿ඪ፯຾ࣴ‫ޑ܌ز‬εߐǴԶգॺ‫ߞޑ‬ҺᆶፊှǴᡣ‫ૈך‬ ӼЈԾӧӦֹԋࣴ‫܌ز‬໘ࢤ‫ޑ‬Ꮲ཰Ǵࡐଯᑫૈ྽೭ሶ෇‫ޑ‬Р҆ ‫ٽޑ‬ηǴ‫׆‬ఈಁ‫ٽ‬ηؒᡣգॺѨఈǹӢࣁஆ࠷Զ੮ӺѠύǵҺ മҺ࡜ǵ࡛か࣮೿۩ᅽ‫ޑ‬ཥஆλॵα -‫ۆۆ‬णৎᆗᆶ‫ۆ‬ϻᐽՎ ᓪǴգॺӧৎ္‫ޑ‬೭ࢤਔ໔ᔅΑ‫ך‬ӳӭӳӭԆǴЀ‫߻ځ‬٤Вη ҅ॶ‫ך‬౥཰‫ۑ‬Ǵգॺࡑӧৎ္ᡣ‫ך‬ёаคࡕ៝ϐኁ‫ܫ‬ЈӦѐჴ ᡍ࠻ǴԖգॺ੿ӳǴઔѠܿғࢲ΋ϪѳӼ໩ၱǹᕴࢂૈඓඝৎ ৥਻‫ݗ‬ǵ൤Ԗεஒϐ॥ǵҞ߻ࣁΑΓғӧᏟରѺ࡫ύ‫ޑ‬ঢঢण ৎᇬ (ࢅ㗄)Ǵջ٬࣬ೀਔ໔ϿΑǴ‫ך‬ᗋࢂ΋‫ߞ࣬ޔ‬գ཮ࢂࢌӚ зΓᢌό๊αǵ‫ڊ‬Ҟ࣮࣬‫ޑ‬εΓ‫ނ‬ǴӢࣁգࢂ‫ך‬ঢߓǴઔգѺ ࡫٣཰ǵΓғਓ೼ຫ‫و‬ຫ໩Ǵу‫ݨ‬Ǽ. -----------------------------------ࡕ૶-------------------------------------ᕴᆉǴፕЎֹԋΑǴΨж߄‫ך‬೭‫ٿ‬ԃ‫ޑ‬ਓ೼ջஒჄ΢΋Ӛ ҶЗ಄ǴቪΑࡐӭᖴᜏǴӢࣁ೭ჹ‫ٰך‬ᇥࡐख़ाǴ‫܈‬೚ፕЎ‫ޑ‬ ϣ৒όૈᅰӵΓཀǴՠ‫ך‬ዴჴ޸Αਔ໔ၟЈՈѐֹԋѬǶ‫ٿ‬ԃ III.

(5) ߻Ǵᗋགྷୂୂ‫ע‬εᏢ౥཰᛾ਜҬ๏ծ‫א‬ፐǴӢࣁࣴ‫܌ز‬٠ό֎ Ї‫ך‬Ǵόၸӣགྷၸѐ೭‫ٿ‬ԃ‫ޑ‬ᗺᗺᅀᅀǴᡣ‫ך‬ᕇளࡐӭܿՋǵ Αှࡐӭ٣௃ǴόፕࢂᏢೌ΢ǵғࢲ΢‫ޑ‬ᅿᅿǴགྷѸᓐတᙁൂǵ ଼‫ב‬ΞҺ‫ךޑ܄‬Ǵ๏εৎబΑόϿഞྠփǴջ٬ӵԜǴ‫ך‬ᗋࢂ ाҺ‫֋ޑ܄‬ນգॺǺඪ‫ב‬Α‫ך‬գॺ൩ֹೈΑǼᖴᖴգॺεৎǴ Ҕ៿ઢǵఽНǵપ੿ǵག୏Ǵࣁ‫ך‬ጓᙃ‫ޑ‬ӣᏫǴ‫ࡐך‬഻៿Ǵ‫ך‬ Ψ཮Ҕλλ‫ޑ‬တ೓ᅰΚ૶Ր‫ঁ؂‬Γ‫؂ޑ‬஭ᖍ‫^_______^ ޑ‬Ǵઔ ‫يך‬ᜐ‫ঁ؂ޑ‬Γ೿ᏱԖឦ‫ܭ‬Ծρ‫ޑ‬ऍ᜽ΓғǴѳӼǵ଼நǶ. IV.

(6) Ҟ. ᒵ. मЎᄔा…………………………………………………………1 ύЎᄔा…………………………………………………………3 ಃ΋ക. 1.1. ᆣፕ ङඳၗ਑…….………………………………………...4. 1.2 2-Phenyl-4-quinolone(2-PQ)ᜪϯӝ‫ނ‬ϐӝԋϷ SAR...11 ಃΒക. ࣴ‫ز‬Ҟ‫ޑ‬ᆶ୏ᐒ……………………………………..14. ಃΟക. ่݀ᆶ૸ፕ. 3.1. 2',3',4'-Substituted 6,7-methylenedioxy-2-phenyl-4quinolones ϐӝԋ……………………...…….……..17 3.2. 6,7-Methylenedioxy-2-(meta-pyridinyl)-4-quinolone ϐӝԋ………….……..……………………………...23. 3.3. 4-Substituted 2'-fluoro-6,7-methylenedioxy-2-phenyl quinolines(2FMPQ)ϐӝԋ………………….........….28 3.4. 6,7-Methylenedioxy-2-(2,3,4-substituted phenyl)4-quinolones ࣬ᜢϐႝတϩηኳᔕ………………....46 ಃѤക ่ፕ…………………………………………………..132. V.

(7) ಃϖക ჴᡍ೽ϩ. 5.1 ၂ᛰᆶྋ൞Ϸ‫׷‬਑………………………….……...133 5.2 ख़ाሺᏔ…………………………………………....139 5.3 ϯӝ‫ޑނ‬ᇙഢ………….…………………………...142 ୖԵЎ᝘………………………………….…………………..187 კ᛼…………………………………...………………….…...193. VI.

(8) Abstract Microtubules are a valid target for anticancer drugs, and it is necessary to continue developing those antimitotic drugs as chemotherapeutic agents. We put the target on researching and synthesizing novel agents for inhibiting cancer cells in our laboratory. At the same time, we found that 2-phenyl-4-quinolone (2-PQ) derivatives were novel antimitotic agents, and most of them were displayed great anticancer activity at large cell lines and some animal experiment. These years, we synthesized a series of 2-PQ derivatives, and chose one of them with excellent anticancer activity for cancer cells as leading compound, 2'-fluoro-6,7-(methylenedioxy)-2-phenyl-4-quinolone (2FMPQ). Therefore, we synthesized 4-substituted derivatives of 2FMPQ to improve the unsatisfying pharmacokinetic characters of 2FMPQ, and expected they could be prodrugs convert to the active form when they are taken into the body in the future. We also put the 6,7-methylenedioxy-2-(2,3,4-substituted phenyl)-4-quinolone analogous to dock into the colchicine binding site of tubulin to discuss and conclude the correlation 1.

(9) between pharmacological parameter and interactions with protein active domain of the series of substituted 2-PQ.. 2.

(10) ύЎᄔा ჹ‫ל‬ᕎᛰ‫ނ‬Զ‫ق‬Ǵ༾λᆅคᅪࢂ΋ঁख़ा‫ޑ‬բҔҞ኱Ǵ Զ࡭ុࣴ‫ز‬Ϸว৖ёҔբϯᏢ‫ݯ‬ᕍ‫לޑ‬Ԗํϩ຋ᛰ‫څࢂނ‬ό ৒጗‫ޑ‬Ƕҁࣴ‫࠻ز‬ஒࣴ‫ز‬Ҟ኱๱ख़ӧ௖૸ᆶӝԋཥᑉ‫לޑ‬ᕎᇙ ᏊǴӕਔว౜‫ڀ‬Ԗ2-phenyl-4-quinolone (2-PQ) ่ᄬ‫़ޑ‬ғ‫ނ‬ ࣣёᘜࣁཥ΋ж‫לޑ‬Ԗํϩ຋ᇙᏊǴԶЪε೽ϩ‫़ޑ‬ғ‫ނ‬ჹε ӭኧᑔᒧ‫ޑ‬ಒझਲ਼೿և౜р‫ؼ‬ӳ‫܄ࢲڋ׭ޑ‬Ǵӧࢌ٤୏‫ނ‬၂ᡍ ҭև౜όᒱ‫לޑ‬ᕎਏ݀Ƕ೭൳ԃǴҁࣴ‫࠻ز‬ҭӝԋΑ΋‫س‬ӈ. 2-PQᜪ़ғ‫ނ‬Ǵ٠Ъவύᑔᒧр΋ന‫ڀ‬ж߄‫܄‬ǴӕਔᏱԖᓬ ‫לذ‬ᕎࢲ‫ޑ܄‬2'-fluoro-6,7-(methylenedioxy)-2-phenyl-4-. quinolone (2FMPQ)բࣁӃᏤϯӝ‫ނ‬ǶӢԜǴҁࣴ‫࠻ز‬Ψ๱Ћ ӝԋΑӧ2FMPQϐಃ4Տ࿼բ‫ڗ‬ж‫࣬ޑ‬ᜢ़ғ‫ނ‬Ǵа‫ׯ‬๓‫ځ‬з Γ၎ੰ‫ޑ‬ᛰ‫୏ނ‬ΚᏢ੝፦Ǵӕਔය೚࣬ᜢ़ғ‫ނ‬ӧ҂ٰё଺ࣁ ߻០ᛰǴ໩ճӧΓᡏϣᙯᡂԋࣁࢲ‫ࠠ܄‬ᄊǶ ନԜϐѦǴ๱‫ޣ‬а΋‫س‬ӈ6,7-methylenedioxy-2-. (2,3,4-substituted phenyl)-4-quinoloneϯӝ‫ނ‬ᆶtubulinϐ colchicine binding site଺dockingǴ٠ஒԜ΋‫س‬ӈᜪ՟‫ނ‬ӧᛰ౛ ኧᏵ‫߄ޑ‬౜Ǵଛӝ‫ځ‬dockingӧ tubulin‫܄ࢲޑ‬೽Տϐ௃‫׎‬Ϸ‫׎‬ԋ ϐբҔΚǴ଺΋࣬ᜢ௖૸ᆶᘜયǶ 3.

(11) ಃ΋ക ᆣፕ 1.1 ङඳၗ਑ ҁፕЎࣴ‫ࢂز‬аӝԋ 2'-fluoro-6,7-(methylenedioxy)-. 2-phenyl-4-quinolone (2FMPQ)ϐᜪጔϯӝ‫ࣁނ‬Ҟ኱Ǵࡺ๱‫ޣ‬ ‫ܭ‬ԜஒӃϟಏᆶ 2FMPQ ‫ڀ‬Ԗ࣬ӕ҆ਡ่ᄬ‫ ޑ‬2-phenyl-4-. quinolone (2-PQ)ᜪϯӝ‫ނ‬ϐ࣬ᜢᛰ౛բҔᐒᙯǵ࣬ᜢᛰ౛ࢲ ‫܄‬ᙁॊǴᆶ‫ځ‬ӝԋБ‫ݤ‬аϷ่ᄬᆶࢲ‫܄‬ᜢ߯(structure activity. relationships; SAR)Ǵ٠а‫ځ‬բࣁҁፕЎࣴ‫ޑز‬ङඳၗ਑Ƕ O 5. O. 4. 6. O. 3 2. 7 8. N1 H. F. 2'. O. 3' 4'. 2-PQ. N H. 2FMPQ. 1.1.1 2-Phenyl-4-quinolone (2-PQ)ᜪ़ғ‫ނ‬ϐ ᜪ़ғ‫ނ‬ϐҗٰᆶ SAR ҁჴᡍ࠻ࣴ‫ ز‬2-phenyl-4-quinolones ςԖӭԃǴว౜‫ځ‬ ‫ڀ‬Ԗᓬຫ٠Ъॶள௖૸‫לޑ‬༾ᆅᆫӝ (inhibition of tubulin. polymerization)ಒझठࢥࢲ‫(܄‬cytotoxity)Ǵ‫ࢂܭ‬ௗ๱а 2-phenyl-4-quinolones ࣁ҆ਡ่ᄬǴٰӝԋ࣬ᜢ‫س‬ӈ़ғ‫ނ‬Ǵ 4.

(12) ӵӧ 2', 3'аϷ 4'Տ࿼΢଺‫ڗ‬ж‫ ޑ‬6,7-methylenedioxy-2. -phenyl-4-quinolone ‫س‬ӈǴٰᑔᒧр‫ڀ‬Ԗᓬ‫לذ‬ᕎࢲ‫܄‬ϐӃᏤ ϯӝ‫ނ‬Ǵ٠຾΋‫่଺؁‬ᄬ΢‫ޑ‬অႬаයૈࣴวр‫ڀ‬Ԗᖏ‫׉‬ਏ ੻‫לޑ‬ᕎᛰ‫ނ‬Ƕ ਥᏵЎ᝘ࡰр 1Ǵ2-phenyl-4-quinolones ᜪғ‫ނ‬ᡵࣁ޼३ ࣽ (Rutaceae) ෌‫ނ‬ϐ੝ԖԋϩǴ‫ ܭ‬1891 ԃ೏ Beckurts Мൂᚆ ࡕ Ǵഌ ഌុ ុԖ ೚ӭ Ꮲ‫ ޣ‬வ٣࣬ᜢ ԋϩ ϐϩ ᚆπ բǴ Զ. Conrad МϷ Limpach Мஒ‫ځ‬ӝԋБ‫ ܭݤ‬1887 ԃջς೏҅Ԅ ว߄ 2,3Ƕ ‫ځ‬Б‫ݤ‬ӵ Scheme 1 ‫܌‬ҢǴarylamine ᆶ β-ketoester ຾Չ ᕭӝϸᔈёғԋ arylaminoacrylateǴௗ๱ӧ diphenyl ether ύ ຾ Չ ዗ ᕉ ϯ (thermal cyclization) Ǵ Զ ‫ ׎‬ԋ Α Ӛ ᅿ ‫ ڗ‬ж ϐ. quinolonesǴόၸ྽߃Ꮲ‫ޣ‬ஒ่ᄬ‫ ࣁۓ‬quinolinesǴ࿶ၸ౜ж ϩ‫݋‬ሺᏔ᠘‫ۓ‬ϐࡕǴ‫҅ځ‬ዴ่ᄬᔈࣁ quinolones Ǵ೭ࢂ२ԛ ว߄ӝԋ quinolones ‫ޑ‬Б‫ݤ‬ǹ‫ࡕځ‬ԖόϿᏢ‫ޣ‬ଞჹ၀ϸᔈϐ ୋౢ‫ނ‬Ϸౢ౗଺௖૸ǴԶஒ Conard-Limpach ϐБ‫ݤ‬уа‫ׯ‬ ๓ǴᔈҔ‫ܭ‬྽ਔว߄‫ޑ‬Ӛᅿ 2-phenyl-4-quinolones ғ‫ނ‬ᡵϐ ӄӝԋǴҭԖ೚ӭᏢ‫ޣ‬ගрӚᅿӝԋ quinolone ᜪ़ғ‫ޑނ‬೼ ৩ǴԶ࣬ᜢᛰ౛ࣴ‫ز‬ൔ֋ǴΨഌុ೏ว߄ǴхࡴߥៈϣҜಒ झࢲ‫ ܄‬4,5ǵ‫ל‬ว‫ݹ‬ǵ‫ל‬Ոλ݈Ꮙ໣ǵ‫ל‬Јࡓό᏾Ϸᓬຫ‫ޑ‬ಒ झࢥఠࢲ‫ ܄‬6-12Ƕ 5.

(13) Scheme 1 O. O. OR". OR" CHR'. CHR'. ΝΗ2 O. N. R. R. OH R' N. R. ӧ 1986 ԃǴC. C. Cheng ࣴ‫ز‬Ꮲ‫ࡰޣ‬р‫ڀ‬ԖΟᕉϯᏢ่ ᄬኳԄ(tricyclic chemical structural pattern)‫ޑ‬ϯӝ‫ނ‬ǴԖ‫ל‬ဍ ዦࢲ‫(܄‬antineoplastic activity)‫ޑ‬ወΚ. Ǵ‫่ځ‬ᄬӵ Fig. 1 ‫܌‬. 13. ҢǶԜ่ᄬ੝ቻࣁӧᚈᕉ naphthalene ҆ਡϐಃ 2 Տ࿼ௗ΢. phenyl ring ୷ი (A)Ǵ‫ࢂޣ܈‬ஒ naphthalene аӚԄӚኬᚇᕉ ൂϡ (heterocyclic units)‫ڗ‬жԶԋ‫ޑ‬ᚈᕉ‫س‬಍Ǵӵ tricin (B)Ϸ. kaempferol (C)Ǵҭ‫ڀ‬Ԗ‫ל‬ဍዦࢲ‫܄‬ǶԶ tricin (B)Ϸ kaempferol (C)‫ࢂ׳‬२ӃԾϺฅ෌‫ڗނ‬ள‫ޑ‬໳✉ᜪ(flavonoids)ϯӝ‫ނ‬ǴѬ ॺ ࣣ ‫ ڀ‬Ԗ ‫ ँ ڋ ׭‬ᡂ (antimutagenic)14 ǵ а Ϸ ‫ ל‬қ Ո ੰ. (antileukemic)15 ฻ࢲ‫܄‬Ƕ OH O. HO. O. OCH3 OH OCH3. A. B 6.

(14) OH O H3CO. OH O. OCH3. OH. H3CO HO. O OCH3. O. OCH3 OH. OH. C. D. Fig. 1 Tricyclic chemical structural pattern 1995 ԃǴҁჴᡍ࠻೸ၸ࣬ᜢࣴ‫ز‬ள‫ޕ‬΢ॊᛰ౛ࢲ‫܄‬ᆶ༾ ᆅೈқ(microtubles)‫࣬ޑ‬ᜢ‫܄‬Ǻ ว౜‫ ډ‬Fig. 1 ύ‫ ޑ‬3',5-dihydroxy-4',3,6,7,8-. pentamethoxy flavonone (D)‫ڀ‬ԖமΚ‫ ڋ׭‬colchicine ᆶ༾ᆅೈ қ่ӝ(inhibition of colchicine binding; ICB)ϐբҔࢲ‫ ܄‬9,16Ƕ. 1993 ԃǴ೾ਠߏаϺฅࣚӸӧϐ flavonoid ࣁ୷ҁମࢎǴ ೛ी٠ӝԋ΋‫س‬ӈ 2-phenyl-4-quinolones ़ғ‫ނ‬Ǻ O. O Design & synthesize. 5. R. 3 2. 7. O. 4. 6. 8. N1. 2' 3'. R1. 4'. R'. Flavonoid. 2-PQ analogues. ӢԜǴҁჴᡍ࠻ஒ(D)ϯӝ‫ ނ‬flavonoid ᕉ΢‫਼ޑ‬চηа ේচηඹжǴ৖໒೛ी٠ӝԋ΋‫س‬ӈ 2-phenyl-4-quinolones 7.

(15) (2-PQ)ᜪጔϯӝ‫ނ‬Ǵӕਔᆶ K. H. Lee Ϸ E. Hamel ฻Ꮲ‫ޣ‬ӝ բǴჹཥӝԋр‫ޑ‬΋‫س‬ӈ 2-PQ ᜪጔϯӝ‫ނ‬຾Չ cytotoxicityǵ. ICB(inhibition of colchicine binding)Ϸ ITP(inhibition of tubulin polymerization)฻ᛰ౛ࢲ‫܄‬ෳ၂ǹ࿶ၸᛰ౛ᐒᙯ௖૸ࣴ‫ز‬Ǵว ౜ҁᜪϯӝ‫ނ‬ϐᛰ౛բҔኳԄᆶ colchicine ่ӝԿ༾ᆅೈқ ϐ௃‫࣬׎‬՟Ǵόၸӧ ITP Ϸ ICB ‫ࠅزࣴޑ‬٠҂և౜࣬ჹᔈϐ ᜢ߯ 16Ƕ ҁჴᡍ࠻‫ૼہ‬ऍ୯ NCI (National Cancer Institute)а. patterns of differential cytotoxicity toward human tumor cell lines ‫ޑ‬БԄٰዴᇡ 2-PQ ᜪጔϯӝ‫ނ‬ϐբҔኳԄǶ࿶ၸࣴ‫ز‬Ǵ ௢ෳҁᜪϯӝ‫ނ‬ឦ‫ڀܭ‬ԖཥᑉϯᏢ่ᄬኳԄ‫לޑ‬ಒझԖํϩ ຋ᇙᏊ(antimitotic agents)17ǶќѦǴҁჴᡍ࠻Ψ‫ܭ‬௖૸ PQ ‫س‬ ӈϯӝ‫ނ‬ϐӝԋϷғ౛ࢲ‫܄‬ਔᢀჸ‫ډ‬Ǵࢌ٤़ғ‫ڀނ‬Ԗ‫ל‬Ո λ݈Ꮙ໣ǵ‫ל‬ว‫ݹ‬ǵ‫ל‬Јࡓό᏾Ϸᓬຫ‫ޑ‬ಒझࢥఠࢲ‫܄‬Ǵ຾ ԶࡌҥΑ่ᄬᆶ࣬ᜢᛰ౛ࢲ‫܄‬ᜢ߯ 6-12ǹҗ‫ܭ‬ҁᜪϯӝ‫ނ‬և౜ рӭኬϯ‫ޑ‬ᛰ౛ࢲ‫܄‬Ǵࡺҁჴᡍ࠻ഌុӝԋΑ‫׳‬ӭᜪጔϯӝ ‫ނ‬Ǵӵ: DHPQ (2,3-dihydro-2-phenyl-4-quinolones)ǵ PQZ. (2-phenylquinazolin- 4-one)ǵDHPQZ (2,3-dihydro-2phenylquinazolin-4-one)] ǵPN (2-phenyl-1,8-naphthyridin -4-one)9,16,18,19 (Fig. 2). 8.

(16) O 5. O 5. 4. 4. 3. 6. 3. 6. R N1 R1. 7 8. R. 2'. 2. 2. 2'. N1 R1. 7. 3'. 8. 4'. 3' 4'. R'. R'. PQ. DHPQ O. O 5. 5. 4 3. NH. 6. R 7 8. R. 2'. 2. N1. 3. 2. 7. 3'. 4. NH. 6. 8. 4'. N1 H H. 2' 3' 4'. R'. R'. PQZ. DHPQZ O 5. 4 3. 6. R 7. 2. N8. N1 R1. 2' 3' 4'. R'. PN Fig. 2 2-phenyl-4-quinolone analogues. Ԝᜪϯӝ‫่ޑނ‬ᄬᆶࢲ‫܄‬ᜢ߯ᙁॊӵΠǺ PQ ᜪጔϯӝ ‫่ޑނ‬ᄬ੝ቻ΢‫ޑ‬Ьाࢎᄬࣣ‫ڀ‬Ԗ΋ঁ biaryl ‫س‬಍ǴѬࢂҗ. A ᕉϷ C ᕉ(ΠБߕკ)‫܌‬ಔӝԶԋ‫ޑ‬ǴԶ A ᕉᆶ C ᕉϐ໔೯ தࢂ࿼Ε΋ঁ B ᕉٰ଺ሒௗ‫ࢂ܈‬ᙖҗᙁൂ‫ޑ‬ᅹణᗖᐏೱௗӧ ΋ଆǶӕਔ࿶ၸࣴ‫૸ز‬ፕว౜Ǵӧ A ᕉ‫ ޑ‬6ǵ7 Տ࿼аϷ C. 9.

(17) ᕉ‫ ޑ‬3'Տ࿼ऩа஥Ԗ҂ӅҔႝηჹ‫(୷ૈ۔ޑ‬ӵ -Fǵ -NRR′ǵ. -OCH2Oǵ-Clǵ-OCH3ǵ฻)8,9,16,19-21 բ‫ڗ‬жਔǴ၀ϯӝ‫཮ނ‬և ౜ᓬຫϐಒझࢥఠࢲ‫܄‬Ǵӆу΢ 3D ่ᄬ‫ޑ‬᠘‫ۓ‬Ǵऩ A ᕉᆶ. C ᕉ΢ϐ‫୷ૈ۔‬໔‫ޑ‬ຯᚆऊࣁ 10 ~ 11 Å ਔǴ٬ள‫ڀ‬ԖӵԜ่ ᄬ੝‫܄‬ϐϯӝ‫ނ‬Ǵૈᙖҗ೭٤‫୷ૈ۔‬ᆶ༾ᆅࢲ‫܄‬೽Տ‫׎‬ԋϩ η໔‫ޑ‬ణᗖ่ӝǴࡺղᘐ A ᕉᆶ C ᕉ΢ϐ‫୷ૈ۔‬ӧ PQ ᜪϯ ӝ‫ނ‬ϐࢲ‫܄‬΢‫ڀ‬Ԗᡉ๱ϐଅ᝘Ƕ O 5 6. R. 4 3. A. B. 8. N1 R1. 7. 2. 2' 3'. C. 4'. R'. PQ ᜪጔϯӝ‫ނ‬ ᆕӝ΢ॊǴӭԃٰҁჴᡍ࠻೛ी٠ӝԋр΋‫س‬ӈ. 2-phenyl-4-quinolones (2-PQ)ᜪጔϯӝ‫ނ‬Ǵ࿶ᛰ౛ෳ၂ዴჴё ஒ‫ځ‬Ҕբࣁཥᑉϐ‫ל‬Ԗํϩ຋ᇙᏊǴЪԜ‫س‬ӈϯӝ‫ނ‬ϐ‫ڋ׭‬ ༾ᆅೈқᆫӝࢲ‫܄‬ᆶಒझࢥఠբҔҭև౜р҅࣬ᜢǶ. 10.

(18) 1.2 2-Phenyl-4-quinolone(2-PQ)ᜪϯӝ‫ނ‬ ϯӝ‫ނ‬ϐӝԋϷ ӝԋϷ SAR PQ ᜪϯӝ‫ޑނ‬ӝԋБ‫ݤ‬ςว߄ၸǴࡺҁჴᡍ࠻٩ൻ࣬ ӕᏹբ‫؁‬ᡯǴట຾Չ࣬ᜢ़ғ‫ނ‬ϐӝԋǴՠ٠҂ள‫ډ‬ӵЎ᝘ ‫܌‬ว߄ϐౢ౗ 16Ƕҁჴᡍ࠻ӧ࿶ၸӭԛ‫ޑ‬Ѩ௳ᆶ჋၂ϐࡕǴ ஒϸᔈచҹ଺ന፾ϯϐፓ᏾Ǵόၸჹ‫ܭ‬നಖౢ‫ޑނ‬પϯǴ٩ ᙑᗋӧ൨‫؃‬΋ঁᓬ‫ޑؼ‬ϩᚆપϯБԄǶ. 1.2.1. 2', 3', 4'-Substituted 2-phenyl-4-quinolones ӝԋБ‫ݤ‬ २Ӄϟಏӧ 1993 ԃҗҁਠ೾ਠߏ஥ሦჴᡍ࠻‫܌‬೛ीр‫ޑ‬ ‫ٿ‬ᅿӝԋБ‫ݤ‬Ǻ. <Б‫ݤ‬΋> ӵ Scheme 2 16 ‫܌‬ҢǴа 2-acetyl aniline (1)բࣁଆ‫ۈ‬চ ਑Ǵtetrahydrofurane (THF)྽ྋ൞ǵtriethylamine (NEt3)྽ᡵǵ. 0 ʚӇ੎‫ޑ‬ϸᔈచҹΠǴϩձᆶ substituted benzoyl chloride (2) ຾Չᙁൂ‫ڗޑ‬жϸᔈǴள‫ډ‬΋‫س‬ӈύ໔ౢ‫ ނ‬3ǹ೭΋‫س‬ӈύ ໔ౢ‫ނ‬࿶ၸೀ౛ϐࡕǴௗ๱а tert-butanol (t-BuOH)྽բྋ ൞ǵpotassium tert-butoxide (t-BuOK)྽ᡵǵ70 ʚ‫ޑ‬ϸᔈచҹ ΠǴ຾Չϩηϣ‫ޑ‬ᕭӝϸᔈǴಥѐ΋ϩηНǴԶள‫ډ‬ᕉϯࡕ ‫ޑ‬ౢ‫ ނ‬substituted 2-phenyl-4-quinolones (4a)Ƕ. 11.

(19) Scheme 2 O. O. R1. Cl NH2. O R2 R3. 1. O. NEt3. R1 R2. N H. THF, 0 к. 2. R3. 3. O. O O. t-BuOK. R1 R2. N H. R1. t-BuOH, 70 к. R3. 3. N H. R2 R3. 4a. <Б‫ݤ‬Β> ӵ Scheme 3 16 ‫܌‬ҢǴа 2-amino-N,N-diethylbenzoylamide. (5)բࣁଆ‫ۈ‬চ਑Ǵbenzene ྽ྋ൞ǵp-toluenesulfonic acid (p-TsOH)྽໽ϯᏊ‫ޑ‬చҹΠǴϩձᆶ substituted methyl aryl ketone (6)ϸᔈǴྕࡋፓ௓Կ٬ϸᔈౢғ଑ࢬԶ຾Չϩη໔‫ޑ‬ ᕭӝϸᔈǴёள‫ډ‬΋‫س‬ӈύ໔ౢ‫ ނ‬7ǹ೭΋‫س‬ӈύ໔ౢ‫ނ‬࿶ ၸೀ౛ϐࡕǴௗ๱а tetrahydrofuran (THF)྽բྋ൞ǵlithium. diisopropylamide (LDA)྽ᡵǵ-30 ʚ‫ޑ‬ϸᔈచҹΠǴ຾Չϩ ηϣ‫ޑ‬ᕭӝϸᔈǴಥѐ΋ϩηНǴԶள‫ډ‬ᕉϯࡕ‫ޑ‬ౢ‫ނ‬. substituted 2-phenyl-4-quinolones (4b)Ƕ. 12.

(20) Scheme 3 O O O. O. R1. NEt2. O. NEt2 R2. O. p-TsOH. R3 benzene reflux. NH2. R1. O. R2. N. R3. 5. 6. 7. O. O. NEt2 O O. R2. N. O. LDA. R1. THF, -30 к. O. R1 N H. R3. 7. R2 R3. 4b. ҁჴᡍ࠻ӧ߈൳ԃ٠҂௦Ҕ Scheme 3 ύ‫܌‬ϟಏ‫ޑ‬Б ‫ݤ‬Ǵ೭ࢂҗ‫ܭ‬Ǻಃ΋‫؁‬ᡯύ٬Ҕ‫ޑ‬ྋ൞ benzene ࢥ‫܄‬εǴߏ ය٬ҔΠёૈ཮ჹΓᡏ೷ԋӆғ‫܄‬ό‫܄ؼ‬೦Ո‫ޑ‬ᅪቾǹќ ѦǴӧಃΒ‫؁‬ᡯύ‫܌‬٬Ҕ‫ ޑ‬LDA ሽ਱ၨܳ຦ǴЪϸᔈྕࡋ ሡ௓‫ڋ‬ӧ-30 ʚǹϸᢀ Scheme 2 ύϟಏ‫ޑ‬၂Ꮚᆶྋ൞Ǵӧ΋ ૓ჴᡍ࠻ࣣܰ‫ڗܭ‬ளǴԶϸᔈ‫܌‬ሡచҹΨၨ৒ܰၲԋǴࡺҁ ჴᡍ࠻ӧ߈൳ԃӝԋ PQ ᜪ‫़ޑ‬ғ‫ࣣނ‬௦Ҕ Scheme 2 ‫ޑ‬Б ‫ݤ‬Ƕ. 13.

(21) ಃΒക. ࣴ‫ز‬Ҟ‫ޑ‬ᆶ୏ᐒ. 2-PQ ࣬ᜢᜪ՟‫ނ‬Ϸ‫़ځ‬ғ‫ނ‬ӧᡏѦ၂ᡍаϷ೽ϩ୏‫ނ‬၂ ᡍύǴς᛾ܴ‫ڀ‬Ԗಒझࢥఠ‫ޑ‬ᛰ౛ࢲ‫܄‬Ǵҁࣴ‫ࣁ࠻ز‬Αૈ‫׳‬ు ΕΑှ 2-PQ ᜪϯӝ‫ނ‬ϐᛰ౛բҔᐒᙯǴߡ๱Ћѐӝԋа. 6,7-methylenedioxy-2-phenyl-4-quinolone ࣁ҆ਡ่ᄬǵӧ 2-phenyl ᕉ΢ϐ 2', 3'аϷ 4'Տ࿼բ‫ڗ‬ж‫ޑ‬΋‫س‬ӈϯӝ‫ނ‬ 11a-jǴӕਔ჋၂ӧ҆ਡಃ 2 Տ࿼аᚇᕉ଺ୁ᜘ϐ‫ڗ‬ж(15)(Fig. 3)Ǵ٠ஒϐଌෳᛰ౛բҔᐒᙯǶ O. O O O. R1 R2. N H. O. 1N. H. R3. 11a-j a: R1=F, R2=H, R3= H b: R1= Cl, R2= H, R3= H c: R1= OCH3, R2= H, R3= H d: R1= H, R2=F, R3= H e: R1= H, R2=Cl, R3= H. O. 4. N. 2'. 15 f: R1= H, R2= OCH3, R3= H g: R1= H, R2= H, R3=F h: R1= H, R2= H, R3=Cl i: R1= H, R2= H, R3= OCH3 j: R1= H, R2= H, R3= H. Fig. 3 ΋‫س‬ӈ 2-PQ ᜪ़ғ‫ނ‬ ҁჴᡍ࠻Ψ჋၂ஒϯӝ‫ ނ‬11a ϐ 4-ketone ୷იଛӝ. bioisosterism ‫ۺཷޑ‬Ǵа amine ᜪ࣬ᜢ୷იբ‫ڗ‬жǴаӝԋ 4-amine derivatives (E)(Fig. 4)Ǵ٠௖૸၀ᜪϯӝ‫ނ‬ᆶ 2-PQ ᜪ ϯӝ‫ނ‬ӧ SAR ԖՖ࣬ᜢ‫܄‬Ǵќ΋Бय़ΨճҔ amines аቚуҁ. 14.

(22) ᜪϯӝ‫ޑނ‬Нྋ‫܄‬ǴӕਔǴҁჴᡍ࠻Ψ჋၂ӝԋ 11a ϐ 4-ketone ୷იа acetic acid բ‫ڗ‬ж‫ޑ‬Нྋ‫܄‬ϯӝ‫ ނ‬30 (Fig. 4)Ǵ٠ஒϐ ᆶ 4-amine derivatives բ΋Кၨᆶ௖૸Ƕ OH R O O. O. 4. 4. O O. N. O. N. 1. F. F. 2'. R =pyrrolidine, methylpiperazine. E. 30. Fig. 4 ϯӝ‫ ނ‬11a ϐ 4-amines ़ғ‫ނ‬Ϸϯӝ‫ ނ‬30 ԜѦǴ2-PQ ‫س‬ӈϯӝ‫ނ‬ϐྋှࡋࣗৡǴӢԜӧ୏‫ނ‬၂ᡍ ा‫ݙ‬৔ᛰࠔ཮ᎁၶྋှࡋό٫‫ޑ‬ୢᚒǶԖ᠘‫ܭ‬ԜǴ๱‫ޣ‬аԖᓬ ຫᡏѦ၂ᡍᛰ౛ࢲ‫܄‬Ъౢ౗Ψၨଯ‫ ޑ‬11a բࣁ leading. compoundǴᔕӝԋӧ 4-ketone ୷იբ‫ׯ‬ᡂԶள‫ ډ‬4-carbamate derivatives (F)(Fig. 5)Ǵ΋Бय़ճҔ carbamate բࣁೱௗᒃН‫܄‬ ୷იǴаቚуҁᜪϯӝ‫ނ‬ϐྋှࡋǹќ΋Бय़ǴਥᏵЎ᝘ 24Ǵ. carbamate Ϸ carbonate ᜘ᐏё໩ճᘐ᜘Ǵࡺ๱‫ޣ‬ၮҔ prodrug ‫ޑ‬ᢀ‫ۺ‬Ǵ‫׆‬ఈ carbamate ᜘ᐏӧᡏϣНှᘐ຋ࡕǴૈஒ 11a ញ ‫ܫ‬рǴ‫׳‬຾΋‫؁‬჋၂೛ीӝԋ‫ܰ׳‬Нှ‫ ޑ‬carbonate derivative. (G) (Fig. 5)Ǵයࡑวච‫׳‬ӳ‫ޑ‬ᛰ‫୏ނ‬ΚᏢԋਏǶ. 15.

(23) O O O. 4. O. 1N. O. N H. R. O O. F. R F. O. F. O. N. G. Fig. 5 а 2-PQ ࣁਡЈϐ኱‫़ޑ‬ғ‫ނ‬ ନԜϐѦǴҁჴᡍ࠻ࣁΑ௖૸኱‫ޑ‬ϯӝ‫ނ‬ᆶҞ኱ೈқ፦ ϩη໔‫ޑ‬բҔ௃‫׎‬ǴаϷ‫ځ‬բҔΚ‫ޑ‬ኧҞӭჲϷ่ӝՏ࿼ᆶ ᛰ౛ࢲ‫࣬ޑ܄‬ᜢ‫܄‬Ǵ௦Ҕ Discovery Studio ႝတϩηኳᔕ. (molecular modeling)‫س‬಍Ǵஒ߻ॊ΋‫س‬ӈϐ 6,7-methylenedioxy-2- phenyl-4-quinolone (MDPQ)‫ޑ‬ᜪጔϯ ӝ‫ނ‬ᆶ tubulin active sites ଺ dockingǴ٠ᆶ colchicine Ϸ. combretastatin-4 (CA-4)຾ՉКၨǴଛӝᛰ౛ኧᏵ‫زࣴޑ‬Ǵа යૈ‫פ‬рᆎύ‫࣬ޑ‬ᜢ‫܄‬Ǵٰࡌ᝼٠௢ෳҁᜪϯӝ‫ނ‬ӧ҂ٰཥ ᑫϐᛰϯౢ཰၀ոΚ‫ޑ‬Ҟ኱ϷᖿӛǴаբࣁ۳ࡕᛰ‫ނ‬೛ी‫ޑ‬ ߃‫؁‬٩ᏵǶ. O O O. R1 N H. R2 R3. MDPQ. Tubulin structure. 16.

(24) ಃΟക ่݀ᆶ૸ፕ 3.1. 2',3',4'-Substituted 6,7-methylenedioxy-2-phenyl-4quinolones ϐӝԋ ࿶ၸࣴ‫ز‬ᆶ௖૸Ǵҁࣴ‫࠻ز‬،‫ۓ‬௦Ҕ Scheme 2 ϟಏ‫ޑ‬ ӝԋБԄٰ຾Չ኱‫ޑ‬ϯӝ‫ ނ‬2', 3', 4' substituted. 6,7-methylenedioxy-2-phenyl-4-quinolones ϐӝԋǴӵ Scheme 416 ‫܌‬ҢǴҁჴᡍ࠻ஒ Scheme 2 ύ‫ޑ‬ಃ΋‫؁‬ᡯ଺Αঅ‫ׯ‬Ǻஒ ϸᔈ‫ޑ‬ྋ൞а toluene жඹচҁ‫ ޑ‬THF(tetrahydrofuran)Ǵϸᔈ ‫ࡋྕޑ‬ΨஒচӃၨόߡ‫ޑ‬Ӈ੎অ‫ྕ࠻ࣁׯ‬Կ 40 ʚό฻Ƕ. Scheme 4 O. O. O. R1. Cl. O. O R2. O. NEt3. R3 toluene, r.t-40 к. NH2. 8. O. O. 9a-j. R2. N H. R3. 10a-j O. O O O. R1. O N H. O. R1. t-BuOK R2 t-BuOH, 70 к O. N H. R3. 10a-j a: R1=F, R2=H, R3= H b: R1= Cl, R2= H, R3= H c: R1= OCH3, R2= H, R3= H d: R1= H, R2=F, R3= H e: R1= H, R2=Cl, R3= H. R1. 11a-j f: R1= H, R2= OCH3, R3= H g: R1= H, R2= H, R3=F h: R1= H, R2= H, R3=Cl i: R1= H, R2= H, R3= OCH3 j: R1= H, R2= H, R3= H. 17. R2 R3.

(25) ӵ Scheme 4 ‫܌‬ҢǴҁჴᡍ࠻а 2-acetyl-4,5-(methylene-. dioxy)aniline(8)ࣁଆ‫ۈ‬চ਑ǵtoluene ࣁྋ൞ǵtriethylamine ྽ ᡵǴϩձᆶӭᅿόӕ‫ڗ‬ж‫ ޑ‬benzoyl chloride(9a-j)ϸᔈǴྕࡋ ௓‫ڋ‬ӧ࠻ྕԿ 40 ʚό฻(ຎϸᔈ‫܄‬Զ‫ۓ‬Ǵऩ࠻ྕΠϸᔈ 1 λ ਔа΢চ਑ϝฅᗋූᎩ೚ӭǴ߾уྕԿ 40 ʚ)ǹಃ΋‫؁‬ᡯࢂ ຾ Չ ᙁ ൂ ‫ ޑ‬ᒃ ਡ ‫ ڗ ܄‬ж ϸ ᔈ Ǵ ٬ Ҕ 2-3 ७ ྽ ໆ ‫ޑ‬. triethylamineǴ΋Бय़ගଯଆ‫ۈ‬চ਑‫ޑ‬ϸᔈ‫܄‬Ǵ΋Бय़ύ‫ک‬ϸ ᔈၸำύ‫܌‬ౢғ‫ ޑ‬1 ྽ໆ HClǹԶ೯தԜ‫؁‬ᡯϸᔈύ benzoyl. chlorides (9a-j)‫܌‬٬Ҕ‫ޑ‬྽ໆኧǴεऊࢂଆ‫ۈ‬চ਑ (8)‫ ޑ‬1.5 ७Կ 3 ७ό฻Ǵω཮٬ϸᔈֹӄǶ Ԝ ΋ ‫ س‬ӈ ύ ໔ ౢ ‫ ނ‬10a-j ‫ ޑ‬પ ϯ Б Ԅ ҭ ё ٬ Ҕ. acetonitrile ଺ӆ่඲Ǵ඲ࠠεӭև౜ଞ‫่ރ‬඲Ǵόၸ฻ࡑਔ ໔ၨߏЪౢ౗ၨեǴࡺ๱‫ޣ‬ӧԜ΋પϯ‫؁‬ᡯόத௦Ҕӆ่ ඲ǴԶࢂ໼ӛӧϸᔈֹԋࡕǴ଺߃‫؁‬ೀ౛٠аѲМᅅЏ‫਻ܜ‬ ၸᘠǴӆҔӇᇃᚖНϷ methanol кϩࢱᅗᘠሪǴஒᘠሪ‫ܫ‬Ε ੿‫ޜ‬ଳᔿጃύଳᔿջёǶ Ԝ‫س‬ӈϯӝ‫่ޑނ‬ᄬ᠘‫ۓ‬а 10a ࣁ‫ٯ‬Ǻ. IRკ᛼(კ1-1) νmax (KBr) cm-1Ǻ‫ܭ‬1610 cm-1ೀԖ‫ޱ‬३‫(܄‬C=C) ՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬1651 cm-1ೀԖ (C=O)՜৖ਁ୏֎ԏঢ়Ǵ ‫ܭ‬2926 cm-1ೀԖႫ‫(ک‬C-H)՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬3196 cm-1ೀԖ ҂Ⴋ‫ޱک‬३‫(܄‬C-H)՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬3390 cm-1ೀԖ(N-H) 18.

(26) ՜৖ਁ୏֎ԏঢ়ǹ߻ॊ੝ቻࣣ಄ӝҁϯӝ‫ނ‬ӧ IRკ᛼‫߄ޑ‬౜Ƕ ፦᛼(EIMS) (კ1-2)Ǻϩηᚆηঢ়ࣁ(m/z 301.2)Ǵᆶϯӝ‫ނ‬ϩη ԄC16H12FNO4࣬಄Ƕ 1. H-NMR (CDCl3-d1Ǵ200 MHz) δ (ppm) (კ 1-3)Ǻ12.79 (1 H, d,. J = 5.2 Hz, NH)Ǵ8.56 (1 H, s, H-3)Ǵ8.02-7.94 (1 H, m, H-4')Ǵ 7.35-7.44 (1 H, m, H-5)Ǵ7.29-7.12 (3 H, m, H-7, H-3', H-6')Ǵ6.04 (2 H, s, CH2)Ǵ2.57 (3 H, s, COCH3)ǹԜϯӝ‫ނ‬ϐNMRణ᛼ᡉ ҢణኧᆶႣය࣬಄ӝǴЪӧ੝ቻૻဦೀҭև౜҅ዴ‫ޑ‬ణኧᆶଽ ӝ߄౜Ƕ 13. C-NMR (CDCl3-d1Ǵ50 MHz) δ (ppm) (კ 1-4)Ǻ200.2Ǵ. 162.9Ǵ152.7Ǵ142.9Ǵ138.5Ǵ133.5Ǵ133.4Ǵ131.5Ǵ124.7Ǵ 124.6Ǵ116.8Ǵ116.3Ǵ109.8Ǵ102.5Ǵ28.6ǹҁϯӝ‫ނ‬ϐᅹ᛼ ᡉҢϐᅹኧᆶႣය࣬಄ӝǶ ᆕӝ΢ॊၗ਑Ǵёዴᇡϯӝ‫ ނ‬10aǴዴჴࣁ N-(2-fluoro-. benzoyl)-6-acetyl-3,4-(methylene -dioxy)anilineǶ ዴᇡϯӝ‫ ނ‬10a-j ϐࡕǴ ǴಃΒ‫؁‬ᡯࢂа t-BuOH ྽ྋ ൞ǵt-BuOK ྽ᡵǵྕࡋ௓‫ڋ‬ӧ 70 ʚǴ٬‫ځ‬຾Չϩηϣᕉϯǹ ‫ځ‬ύ‫܌‬٬Ҕ‫ޑډ‬ᡵ t-BuOKǴਥᏵᢀჸᆶइᒵ่݀Ǵ‫܌‬٬Ҕϐ ྽ໆኧεऊࢂϸᔈ‫(ނ‬10a-j)‫ ޑ‬3.5-5 ७ਔǴ཮٬ளϸᔈၨᖿ‫ܭ‬ ֹӄǹќѦ‫ݙ‬ཀ‫ ࢂޑ‬t-BuOK ܰ֎ዊǴ‫܌‬аӧ٬Ҕਔाᅰ‫ז‬ 19.

(27) уΕϸᔈ౟ύǴᗉխӢࣁ֎ዊ௃‫׎‬ϼᝄख़Զቹៜϸᔈ‫ޑ‬໩ճ ຾ՉǶ ќ΋ঁз๱‫ޣ‬ག‫ډ‬Ԗ፪‫ࢂޑ‬Ǵ྽ଆ‫ۈ‬চ਑(8)ᖼԾऍ୯. Aldrich ϦљǴ‫ځ‬ϩηϣᕉϯ‫؁‬ᡯ‫܌‬ሡਔ໔ऊࣁ 20-24 hrǴߡ ё٬ύ໔ౢ‫(ނ‬10a-j)кϩϸᔈֹӄǹόၸǴ྽ଆ‫ۈ‬চ਑(8)ࣁ ᖼԾऍ୯ Acros Ϧљ‫ޣ‬Ǵӕ΋‫؁‬ᡯࠅሡा຾Չ 48 ‫ ࢂ܈‬72 λ ਔࣗԿ‫ޑߏ׳‬ਔ໔Ǵౢ౗ҭό‫ـ‬ளԖ߻‫׳ޑٰޣ‬ଯǶ᠘‫ܭ‬Ԝ ΋௃‫׎‬Ǵ๱‫ޣ‬ҭѐ჋၂ΑஒᖼԾ‫ٿ‬Ϧљ‫ޑ‬ଆ‫ۈ‬চ਑բ߃‫؁‬ϩ ‫݋‬КၨǺAldrich Ϧљ‫ޑ‬চ਑ࣁ 98 %ǴAcros Ϧљ‫߾ޑ‬҂኱Ң પࡋǴԶ‫ޣٿ‬ӧ TLC ᎑Т΢‫܌‬ᡉҢϐ Rf ॶคৡ౦Ǵ୤ Acros Ϧљ‫ޑ‬চ਑ӧвಒᢀჸΠǴӧ Rf ॶౣեೀԖ΋ߚத఩ UV ֎ ԏ‫ޑ‬λᗺǹࡺ߃‫؁‬௢ፕ཮Ԗϸᔈ‫܌‬ሡਔ໔ߏอৡຯ೭ሶε‫ޑ‬ চӢϐ΃Ǵᔈࣁ၀চ਑ӧપࡋ΢Ԗ‫܌‬ৡ౦‫܌‬೷ԋǶӢԜǴ๱ ‫ޣ‬ஒόӕቷจ(Aldrich, Acros)ϐଆ‫ۈ‬চ਑Ǵ‫ୖ܌ځ‬ᆶӝԋϯ ӝ‫ ނ‬11a ϐ࣬ᜢϸᔈచҹᆶౢ౗ӈ‫ܭ‬Π߄(Table 1)Ǵа੣К ၨǺ. Table 1. ӝԋ 11a ϐ࣬ᜢϸᔈచҹᆶౢ౗ Company. Temperature (ʚ). Duration(hr). Yield(%). Aldrich. 70. 24. 66. Acros. 70. > 72. 40. Aldrich. 85. ~ 20. 66. Acros. 85. 60-72. 45. 20.

(28) җ Table 1 ё‫ޕ‬Ǵ྽௦Ҕ Aldrich Ϧљϐଆ‫ۈ‬চ਑ӝԋϯ ӝ‫ ނ‬11aǴϸᔈྕࡋϩձࣁ 70 ᆶ 85 ʚǴϸᔈ‫܌‬ሡਔ໔ঁձ ࣁ 24 hr Ϸஒ߈ 20 hrǴᕉϯ‫؁‬ᡯϐౢ౗֡ёၲ‫ ډ‬66 %ǹԶ྽ ๱‫ޣ‬௦Ҕ Acros Ϧљϐଆ‫ۈ‬চ਑ࡕǴӕኬஒϸᔈྕࡋ௓‫ڋ‬ӧ. 70 ᆶ 85 ʚǴϸᔈਔ໔ࠅϩձሡाε‫ ܭ‬72 hr аϷ 60-72 hrǴ ᕉϯ‫؁‬ᡯౢ౗ΨѝԖ 40 Ϸ 45 %Ƕ ӢԜǴ๱‫ࡌޣ‬᝼۳ࡕ຾Չჴᡍ߻ǴᔈଞჹϸᔈӚ‫؁‬ᡯ‫ޑ‬ চ਑ǵ၂Ꮚբ߃‫ޑ؁‬ϩ‫݋‬᠘‫ۓ‬аϷપϯǴаᗉխϸᔈύόપ ‫ނ‬፦ቹៜΑϸᔈ‫ޑ‬຾ՉаϷౢ౗Ƕ. 11a-j ϯӝ‫่ޑނ‬ᄬ᠘‫ۓ‬а 11a ࣁ‫ٯ‬Ǻ IRკ᛼(კ2-1) νmax (KBr) cm-1Ǻ‫ܭ‬1610 cm-1ೀԖ‫ޱ‬३‫(܄‬C=C) ՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬1625 cm-1ೀԖ (C=O)՜৖ਁ୏֎ԏঢ়Ǵ ‫ܭ‬2953 cm-1ೀԖႫ‫(ک‬C-H)՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬3053 cm-1ೀԖ ҂Ⴋ‫ޱک‬३‫(܄‬C-H)՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬3460 cm-1ೀԖ(N-H) ՜৖ਁ୏֎ԏঢ়ǹ߻ॊ੝ቻࣣ಄ӝҁϯӝ‫ނ‬ӧ IRკ᛼‫߄ޑ‬౜Ƕ ፦᛼(EIMS) (კ2-2)Ǻϩηᚆηঢ়ࣁ(m/z 283.0)Ǵᆶϯӝ‫ނ‬ϩη ԄC16H10FNO3࣬಄Ƕ 1. H-NMR (DMSO-d6Ǵ200 MHz) δ (ppm) (კ 2-3)Ǻ11.79 (1 H, br. s, NH)Ǵ7.73-7.53 (2 H, m, H-3',H-6')Ǵ7.45-7.34 (3 H, m, H-5, H-4', H-5')Ǵ7.09 (1 H, s, H-8)Ǵ6.15 (2 H, s, CH2)Ǵ6.12 (1 H, s, 21.

(29) H-3)ǹԜϯӝ‫ނ‬ϐNMRణ᛼ᡉҢణኧᆶႣය࣬಄ӝǴЪӧ੝ ቻૻဦೀҭև౜҅ዴ‫ޑ‬ణኧᆶଽӝ߄౜Ƕ 13. C-NMR (DMSO-d6Ǵ50 MHz) δ (ppm) (კ 2-4)Ǻ151.7Ǵ. 145.9Ǵ133.0Ǵ132.4Ǵ131.2Ǵ125.4Ǵ117.0Ǵ116.6Ǵ102.4Ǵ 101.3Ǵ86.1Ǵ80.1Ǵ79.4Ǵ78.8ǹҁϯӝ‫ނ‬ϐᅹ᛼ᡉҢϐᅹኧ ᆶႣය࣬಄ӝǶ ᆕӝ΢ॊၗ਑Ǵёዴᇡϯӝ‫ ނ‬11aǴዴჴࣁ 2'-fluoro-6,7-. methylenedioxy-2-phenyl-4-quinoloneǶ. 22.

(30) 3.2. 6,7-Methylenedioxy-2-(meta-pyridinyl)-4-quinolone (15) ϐӝԋ ҁჴᡍ࠻ҭ჋၂Αӝԋӧ quinolone ‫ޑ‬ಃ 2 Տ࿼΢а. pyridine ୷იբ‫ڗ‬ж‫ޑ‬ϯӝ‫ނ‬ǴӧԜஒ‫ځ‬ӝԋБ‫ݤ‬၁ॊӵΠǺ २ Ӄ ࢂ ᇙ ഢ nicotinyl chloride Ǵ ӵ Scheme 522 ‫ ܌‬Ң Ǵ ஒ. nicotinic acid (12) ‫ ޔ‬ௗ ᆶ thionyl chloride (SOCl2) ຾ Չ chlorination Զள‫ ډ‬nicotinyl chloride (13)Ƕ Scheme 5 O. O. SOCl2. HO. Cl N. reflux. 12. N. 13. ӧ Scheme 5 ύ‫ޑ‬ϸᔈచҹሡӧคН‫ޑ‬ᕉნΠ຾ՉǴӢ ࣁНϩ཮٬ள thionyl chloride ϩှ٠ᇙ೷рᡶለǴό໻ϸᔈ ਏ౗ε෧ǴΨ཮೷ԋόѸा‫ޑ‬Ӓᓀ‫܄‬ǹќѦǴӧϸᔈ่‫״‬ਔ ा౽ନεໆӭᎩ‫ޑ‬ለ‫ނ܄‬፦ thionyl chloride ਔǴऩҔ෧ᓸᐚ ᕭᐒ‫ܜ‬ନǴϝԖ೽ϩ‫ ޑ‬thionyl chloride ཮‫ޔ‬ௗ೏‫ܜ‬຾ၮଌ‫ޑ‬ ᆅጕύ೷ԋᆅጕ৒ܰૄ຋ǴԶᐒᏔύ௽ᙯື‫ޑ‬პТΨ৒ܰ೏ ᆭᇑԶ೷ԋᐒᏔᑃཞǹҁჴᡍ࠻‫ޑ‬ೀ౛БԄǴࢂӧၮଌᆅጕ ന߻ᆄу΋ঁးԖ NaOH ྋన‫ޑ‬ᡵ‫܄‬጗ፂ౟ǴԜೀ NaOH(S) ऊౣ௓‫ࣁڋ‬ለ‫ ޑ‬2-3 ७྽ໆϐӭǴаዴߥᡵనԖ‫ૈ୼ى‬Κஒ 23.

(31) εໆ‫ޑ‬ለύ‫ک‬௞Ǵለᡵύ‫ܫ཮ک‬рεໆ‫ޑ‬዗ǴሡλЈᏹբǶ ‫ڗ‬ள nicotinyl chloride (13)ϐࡕǴाᅰ‫ז‬۳Π΋‫؁‬ᡯ຾ ՉǴӢࣁҁ‫ނ‬፦‫ܫ‬Φ཮ᡂӣ nicotinic acid (࿶ၸϩ‫݋‬ዴ‫)ۓ‬Ǵ ࡺҞ߻௢ෳΨ೚ࢂӢࣁ‫਻ޜ‬ύ‫ޑ‬НϩᏤठ‫ځ‬วғ਼ϯ‫ޑ‬௃ ‫׎‬Ƕ ϯӝ‫ ނ‬13 ϐ่ᄬ᠘‫ۓ‬Ǻ 1. H-NMR (DMSO-d6Ǵ200 MHz) δ (ppm) (კ 21-2)Ǻ9.13 (1 H, d,. J = 0.6 Hz, H-2)Ǵ8.96 (1 H, d, J = 4.2 Hz, H-6)Ǵ8.64 (1 H, d, J = 8.0 Hz, H-4)Ǵ7.91 (1 H, dd, J = 5.4, 8.0 Hz, H-5)ǹԜϯӝ‫ނ‬ϐ NMRణ᛼ᡉҢణኧᆶႣය࣬಄ӝǴЪӧ੝ቻૻဦೀҭև౜҅ ዴ‫ޑ‬ణኧᆶଽӝ߄౜Ƕ 13. C-NMR (CDCl3-d1Ǵ50 MHz) δ (ppm) (კ 21-3)Ǻ164.9Ǵ. 148.7Ǵ146.1Ǵ142.5Ǵ129.1Ǵ126.4 ǹҁϯӝ‫ނ‬ϐᅹ᛼ᡉҢ ϐᅹኧᆶႣය࣬಄ӝǶ ௗ๱൩ࢂӝԋ 6,7-methylenedioxy-2-pyridin-3-yl-. 4-quinolone (15)Ǵ೭္‫܌‬௦Ҕ‫ޑ‬Б‫ݤ‬ၟ Scheme 4 ‫܌‬ϟಏ‫ޑ‬٠ คϼεόӕǴ୤΋όӕೀӧ‫ܭ‬ӝԋύ໔ౢ‫ޑނ‬ಃ΋‫؁‬ᡯύǴ ‫܌‬Ҕ‫ޑ‬ϸᔈచҹόӕǴӵ Scheme 620 ‫܌‬ҢǺ. 24.

(32) Scheme 6 O. O. O. O O. NH2. N. 8. O. NEt3. Cl. CH2 Cl2, rt. 13. O. N H. N. 14 O. O O. O O. O. O N H. t-BuOK t-BuOH, 70 к O. N H. N. 14. N. 15. ӵ Scheme 6 ‫܌‬ҢǴҁჴᡍ࠻а 2-acetyl-4,5-. methylenedioxyaniline (8)ࣁଆ‫ۈ‬চ਑ǵdichloromethane ࣁྋ ൞ǵtriethylamine ྽ᡵǴᆶ nicotinyl chloride (13)ϸᔈǴྕࡋ ௓‫ڋ‬ӧ 55 ʚ΢Π(٬ dichloromethane ଑ࢬջё)ǹಃ΋‫؁‬ᡯ຾ Չᙁൂ‫ޑ‬ᒃਡ‫ڗ܄‬жϸᔈǴ٬Ҕ 2-3 ७྽ໆ‫ ޑ‬triethylamineǴ ΋Бय़ගଯଆ‫ۈ‬চ਑‫ޑ‬ϸᔈ‫܄‬Ǵ΋Бय़ύ‫ک‬ϸᔈၸำύ‫܌‬ౢ ғ‫ ޑ‬1 ྽ໆ hydroxy chlorideǹԶ೯தԜ‫؁‬ᡯϸᔈύ nicotinyl. chloride (13)‫܌‬٬Ҕ‫ޑ‬྽ໆኧǴεऊࢂଆ‫ۈ‬চ਑ 8 ‫ ޑ‬1.5 ७Կ 3 ७ό฻Ǵω཮٬ϸᔈֹӄǶ Ԝԛӝԋಃ΋‫؁‬ᡯύ‫܌‬٬Ҕ‫ޑ‬ྋ൞‫ׯ׳‬ԋ. dichloromethane ‫ޑ‬চӢࢂҗ‫ ܭ‬nicotinyl chloride (13)ჹ‫ܭ‬ 25.

(33) dichloromethane ‫ޑ‬ྋှࡋၨ٫Ǵ೭ᗺӧӃ߻ϟಏ‫ ޑ‬Scheme 4 ύ٠҂ᎁၶྋှࡋ‫ޑ‬ୢᚒ(substituted benzoyl chlorides ࣣࣁ నᄊ )Ǵ࿶ၸӭԛ჋၂ᆶѨ௳ࡕǴ๱‫ׯޣ‬ᡂబуϸᔈ‫ޑނ‬Б‫ݤ‬ ω໩ճӝԋϯӝ‫ ނ‬14Ǵ୷‫ ܭ‬13 ࢂ‫ڰ‬ᡏǴा጗ᄌᅀуΕϸᔈ ౟ύό৒ܰၲԋǴЪ 13 ৒ܰ‫ ډڙ‬triethylamine ‫ޑ‬ઇᚯԶញ‫ܫ‬ εໆᡶለ਻ᡏቹៜϸᔈ຾ՉǴ‫܌‬аӧ Scheme 5 ύ‫ڗ‬ள 13Ǵ ଳᔿࡕ‫ޔ‬ௗஒ dichloromethane уΕӕ΋ϸᔈन‫׎‬౟ύǴᒿࡕ уΕଆ‫ۈ‬চ਑ 8 ΋‫ٳ‬ᠳ܏(Ԝషӝྋనᆀࣁ A న )Ǵࡑкϩᠳ ܏ࡕǴӆஒ triethylamine ᆶ dichloromethane ‫ޑ‬షӝన጗ᄌᅀ уΕ A న (Ԝೀ٠҂‫ޔ‬ௗа triethylamine ᅀуԶ௦‫ڗ‬షӝన‫ޑ‬ БԄǴࢂࣁΑᗉխ‫ځ‬аଯᐚࡋᅀΕ A నԶౢғεໆᡶለ਻Ǵ ࿶ၸีញ‫ ޑ‬triethylamineǴӆ጗ᄌᅀΕ A నǴёа෧Ͽᡶለ ਻ᡏ΋ᕓ໔ౢғϼεໆԶቹៜϸᔈਏ౗)Ǵᅀуֹ౥ࡕӆᠳ܏. 5-6 hr ջёǶ ௗΠٰ 14 ‫ޑ‬પϯೀ౛БԄᆶ߻ॊ 10a-j ࣬ӕǴԶᒿࡕಃ Β‫؁‬ᡯ‫ޑ‬ϩηϣᕉϯҭ௦‫ڗ‬ᆶ 10a-j ࣬ӕБԄǴՠࢂౢ౗ܴ ᡉեΑ೚ӭǴҗ TLC Т΢ᢀჸ‫ډ‬Ԝᕉϯ‫؁‬ᡯ֖Ԗ‫ځ‬Ꭹλᚇ ᗺǴЬᗺҭόܴᡉǹ15 પϯБԄΨၨ 11a-j ٰளፄᚇǴӧપ ϯҁϯӝ‫ނ‬ਔǴҗ‫ܭ‬ྋှࡋό٫Ǵҁჴᡍ࠻ҭ჋၂ΑаଳԄ ‫ޑ‬Б‫ٰݤ‬຾Չᆅࢊቫ‫݋‬Ǵՠࢂϩᚆਏ݀٠όӳǴౢ౗ѝԖό ‫ ډ‬10 %Ǵࡺό௦ҔǹќѦҁჴᡍ࠻Ψ჋၂Ҕ DMSO. (dimethylsulfoxide)଺ӆ่඲ǴؒԖ่඲‫݋‬рǴҭό௦ҔԜ‫ݤ‬ǹ 26.

(34) നࡕ௦Ҕ‫ޑ‬પϯБ‫ୖࢂݤ‬Եપϯ 11a-j ‫ޑ‬Б‫ݤ‬ǴճҔ. dichloromethane ᆶ methanol షӝన(d:m=20:1 v/v)у዗଑ࢬǴ ၸᘠࡕ‫ڗ‬ᘠર΢‫ڰޑ‬ᡏǴω৾‫ډ‬ౢ౗ౣଯ΋٤‫ޑ‬ϯӝ‫ ނ‬15. (yield 35 %)Ƕ ϯӝ‫ ނ‬15 ‫่ޑ‬ᄬ᠘‫ۓ‬Ǻ. IRკ᛼(კ23-1) νmax (KBr) cm-1Ǻ‫ܭ‬1523 cm-1ೀԖ‫ޱ‬३‫(܄‬C=C) ՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬1618 cm-1ೀԖ (C=O)՜৖ਁ୏֎ԏঢ়Ǵ ‫ܭ‬2951 cm-1ೀԖႫ‫(ک‬C-H)՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬3059 cm-1ೀԖ ҂Ⴋ‫ޱک‬३‫(܄‬C-H)՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬3446 cm-1ೀԖ(N-H) ՜৖ਁ୏֎ԏঢ়ǹ߻ॊ੝ቻࣣ಄ӝҁϯӝ‫ނ‬ӧ IRკ᛼‫߄ޑ‬౜Ƕ ፦᛼(EIMS) (კ23-2)Ǻϩηᚆηঢ়ࣁ (m/z 266.1)Ǵᆶϯӝ‫ނ‬ϩ ηԄC15H10N2O3࣬಄Ƕ 1. H-NMR (DMSO-d6Ǵ200 MHz) δ (ppm) (კ 23-3)Ǻ11.41 (1 H,. s, NH)Ǵ9.02 (1 H, s, H-5)Ǵ8.70 (1 H, d, J = 1.9 Hz, H-4')Ǵ8.20 (1 H, br s, H-6')Ǵ7.57-7.54 (1 H, m, H-5')Ǵ7.42 (1 H, s, H-2')Ǵ7.18 (1 H, s, H-8)Ǵ6.14 (3 H, br s, CH2)ǹԜϯӝ‫ނ‬ϐNMRణ᛼ᡉҢ ణኧᆶႣය࣬಄ӝǴЪӧ੝ቻૻဦೀҭև౜҅ዴ‫ޑ‬ణኧᆶଽӝ ߄౜Ƕ. 27.

(35) 3.3. 4-Substituted 2'-fluoro-6,7-methylenedioxy-2-phenyl ϐӝԋ quinolines(2FMPQ)ϐӝ ԋ ӝԋ΋‫س‬ӈ‫ ޑ‬2',3',4'-substituted 6,7-methylenedioxy-. 2-phenyl-4-quinolones ϐࡕǴҁࣴ‫࠻ز‬ᑔᒧр΋‫ڀ‬Ԗᓬ‫ذ‬ᡏѦ ‫ל‬ᕎࢲ‫܄‬Ъౢ౗നଯ‫ ޑ‬11a ٰ྽բӃᏤϯӝ‫ނ‬Ǵа‫ׯ‬๓‫ځ‬ᛰ ‫୏ނ‬ΚᏢ੝‫ࣁ܄‬Ҟ኱ǴԶӧಃ 4 Տ࿼‫ ޑ‬ketone ୷იௗ΢όӕ ‫ڗ‬жǴ଺ࣁ 11a ϐ߻០‫ނ‬ǴаයӧᡏϣНှᘐ᜘ԋࣁ 11aǴ ԶวචਏҔǴ๱‫ޣ‬೛ी‫ٿ‬εᜪϯӝ‫ނ‬Ǵ΋ࢂ carbamate-linked. hydrophilic groupǴќ΋ᜪࣁ carbonate-linked hydrophilic groupǴ‫ځ‬ӝԋБԄ‫ࡕܭ‬Ƕ 3.3.1. 2FMPQ ϐ 4-carbamate ़ғ‫ނ‬ϐӝԋ ़ғ‫ނ‬ϐӝԋ 3.3.1.1. 2'-Fluoro-6,7-methylenedioxy-2-phenyl-4(N,N-diethylcarbamoyl)quinoline (17)ϐӝԋ ๱‫ୖޣ‬ԵΑ࣬ᜢЎ᝘ 23,24 ǴӆਥᏵଆ‫ۈ‬ϯӝ‫ ނ‬11a ‫ޑ‬ϯ Ꮲ੝‫܄‬ǴӧӝԋБ‫ݤ‬΢଺Α΋٤অ҅Ǵӵ Scheme 724 ‫܌‬ҢǶ. Scheme 7 O O. O O O. O. F N H. 11a. Cl. N. NaH. O. DMF, 50 к O. 16. F N. 17 28. N.

(36) ӵ Scheme 7 ‫܌‬ҢǴ๱‫ޣ‬аϯӝ‫ ނ‬11a ᆶ N,N-. diethylcarbamoyl chloride (16)ӧ DMF (dimethylformamide)྽ ྋ൞ǵsodium hydride (NaH)྽ᡵǵྕࡋ௓‫ڋ‬ӧ 50 ʚ‫ޑ‬ᕉნ ΠǴ຾Չᙁൂ‫ڗޑ‬жϸᔈǴౢғ΋ϩη‫ޑ‬ᡶለǴӝԋрϯӝ ‫ ނ‬17Ƕ ϯӝ‫ ނ‬17 ‫่ޑ‬ᄬ᠘‫ۓ‬Ǻ. IRკ᛼(კ24-1) νmax (KBr) cm-1Ǻ‫ܭ‬1616 cm-1ೀԖ‫ޱ‬३‫(܄‬C=C) ՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬1710 cm-1ೀԖ (C=O)՜৖ਁ୏֎ԏঢ়Ǵ ‫ܭ‬2875 cm-1ೀԖႫ‫(ک‬C-H)՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬2980 cm-1ೀԖ ҂Ⴋ‫ޱک‬३‫(܄‬C-H)՜৖ਁ୏֎ԏঢ়ǹ߻ॊ੝ቻࣣ಄ӝҁϯӝ ‫ނ‬ӧ IRკ᛼‫߄ޑ‬౜Ƕ ፦᛼(EIMS) (კ24-2)Ǻϩηᚆηঢ়ࣁ (m/z 382.2)Ǵᆶϯӝ‫ނ‬ϩ ηԄC16H10FNO3࣬಄Ƕ 1. H-NMR (DMSO-d6Ǵ200 MHz) δ (ppm) (კ 24-3)Ǻ8.05-8.01 (1. H, m, H-4')Ǵ7.59 (1 H, d, J = 1.9 Hz, H-3')Ǵ7.48-7.43 (2 H, m, H-5, H-5')Ǵ7.38-7.31 (2 H, m, H-3, H-6')Ǵ7.14 (1 H, s, H-8)Ǵ6.23 (2 H, s, CH2)Ǵ3.53 (2 H, q, J = 6.8 Hz, NCH2CH3)Ǵ3.35 (2 H, q, J = 3.7 Hz, NCH2CH3)Ǵ1.30-1.11 (6 H, m, N(CH2CH3)2)ǹԜϯ ӝ‫ނ‬ϐNMRణ᛼ᡉҢణኧᆶႣය࣬಄ӝǴЪӧ੝ቻૻဦೀҭ և౜҅ዴ‫ޑ‬ణኧᆶଽӝ߄౜Ƕ. 29.

(37) 13. C-NMR (DMSO-d6Ǵ50 MHz) δ (ppm) (კ 24-4)Ǻ154.6Ǵ. 152.5Ǵ151.7Ǵ148.8Ǵ131.7Ǵ127.4Ǵ127.1Ǵ125.2Ǵ118.4Ǵ 117.0Ǵ116.5Ǵ113.0Ǵ112.8Ǵ105.9Ǵ102.9Ǵ96.7Ǵ42.5Ǵ42.3Ǵ 14.7Ǵ13.6ǹҁϯӝ‫ނ‬ϐᅹ᛼ᡉҢϐᅹኧᆶႣය࣬಄ӝǶ ӧ Scheme 7 ္‫ޑ‬చҹа DMF ྽ྋ൞Ǵࢂҗ‫ܭ‬ϯӝ‫ ނ‬11a ‫ޑ‬ྋှࡋό٫ǹќѦǴ٬Ҕமᡵ sodium hydrideǴࢂࣁΑᡣ 11a ϐಃ 4 Տ࿼΢‫਼ޑ‬চηૈ‫ڀ׳‬Ԗᒃਡ‫܄‬ǹྕࡋБय़Ǵऩа࠻ྕ Π຾ՉϸᔈҭёǴ୤ϸᔈਔ໔ሡ઻຤ 10-20 hr ࣗԿ‫׳‬ΦǴӆ ࿶ၸჴᡍ่݀ว౜Ǵྕࡋ௓‫ڋ‬ӧ 50 ʚёа٬ϸᔈਏ౗ගϲǴ ϸᔈਔ໔ᕭอ‫ ډ‬3-5 hr (yield 32 %)Ƕ. 3.3.1.2. 2'-Fluoro-6,7-methylenedioxy-2-phenyl-4(4-methyl-1-piperazinecarbonyl)quinoline (19)ϐӝԋ Scheme 8 O O O O. O O. F N H. 11a. +. Cl. N. N. pyridine. O. 140-145 к. O. 18. N. N F. N. 19. ӵ Scheme 824 ‫܌‬ҢǴஒϯӝ‫ ނ‬11a ᆶ 4-methyl-. 1-piperazinecarbonyl chloride (18)Ǵӧ pyridine ྽ᡵΨ྽ԋྋ 30.

(38) ൞‫ޑ‬ϸᔈచҹΠǴ٬у዗ౢғ଑ࢬǴԶள‫ډ‬ϯӝ‫ ނ‬19Ƕ ϯӝ‫ ނ‬19 ‫่ޑ‬ᄬ᠘‫ۓ‬Ǻ. IRკ᛼(კ25-1) νmax (KBr) cm-1Ǻ‫ܭ‬1724 cm-1ೀԖ (C=O)՜৖ ਁ୏֎ԏঢ়Ǵ‫ܭ‬2796 cm-1ೀԖႫ‫(ک‬CH3)՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬. 2922 cm-1ೀԖႫ‫(ک‬CH2)՜৖ਁ୏֎ԏঢ়ǹ߻ॊ੝ቻࣣ಄ӝҁ ϯӝ‫ނ‬ӧ IRკ᛼‫߄ޑ‬౜Ƕ ፦᛼(EIMS) (კ25-2)Ǻϩηᚆηঢ়ࣁ (m/z 409.3)Ǵᆶϯӝ‫ނ‬ϩ ηԄC22H20FN3O4࣬಄Ƕ 1. H-NMR (DMSO-d6Ǵ200 MHz) δ (ppm) (კ 25-3)Ǻ8.08-7.99 (1. H, m, H-4')Ǵ7.63 (1 H, d, J = 2.1 Hz, H-3')Ǵ7.43 (1 H, s, H-5)Ǵ 7.35-7.29 (1 H, m, H-5')Ǵ7.29-7.24 (1 H, m, H-6')Ǵ7.18-7.12 (2 H, m, H-3, H-8)Ǵ6.09 (2 H, s, CH2)Ǵ3.74 (4 H, d, J = 38.3 Hz, H-2'', H-6'')Ǵ2.53 (4 H, d, J = 3.2 Hz, H-3'', H-5'')Ǵ2.37 (3 H, s, NCH3)ǹԜϯӝ‫ނ‬ϐNMRణ᛼ᡉҢణኧᆶႣය࣬಄ӝǴЪӧ੝ ቻૻဦೀҭև౜҅ዴ‫ޑ‬ణኧᆶଽӝ߄౜Ƕ 13. C-NMR (DMSO-d6Ǵ50 MHz) δ (ppm) (კ 25-4)Ǻ154.0Ǵ. 152.1Ǵ151.2Ǵ148.3Ǵ131.3Ǵ130.6Ǵ130.5Ǵ124.5Ǵ118.4Ǵ 115.9Ǵ113.3Ǵ113.1Ǵ106.3Ǵ101.8Ǵ96.6Ǵ54.8Ǵ54.5Ǵ46.1Ǵ 44.6Ǵ44.1Ǵ29.7ǹҁϯӝ‫ނ‬ϐᅹ᛼ᡉҢϐᅹኧᆶႣය࣬಄ӝǶ. 31.

(39) Ӣࣁϯӝ‫ ނ‬18 ᆶϯӝ‫ ނ‬16 ่ᄬԄ࣬՟Ǵࡺ๱‫ޣ‬२Ӄа. Scheme 7 ‫ޑ‬చҹ჋၂ӝԋ 19Ǵࠅ҂ள‫܌ډ‬ሡϯӝ‫ނ‬Ƕ௢ෳ ёૈࢂྕࡋό‫ى‬Ꮴठ 11a ϐಃ 4 Տ࿼΢‫਼ޑ‬চη‫ځ‬ϸᔈ‫܄‬ό ‫ى‬а٬ 18 ่ᄬύ‫ޑ‬ෛᚆηᚆѐǹᅟࡕ๱‫ޣ‬ԵቾҔ‫ڀ‬Ԗᡵ‫܄‬Ъ ‫ݦ‬ᗺ‫׳‬ଯ‫ ޑ‬pyridine ྽ྋ൞Ǵӆஒྕࡋፓ᏾Կౢғ଑ࢬǴϸ ᔈ 10 hrǴTLC ТᢀჸςԖ౦‫ ܭ‬11a ϐќ΋Ьᗺ‫ޑ‬อ‫๋ݢ‬ѦӀ ֎ԏǴӢԜӆз‫ځ‬ϸᔈ 10 hrǴՠ 11a ӧ TLC ТΠև౜‫ޑ‬ᐚ ࡋ٠คᡂ఩ǴӢԜஒϸᔈύЗ٠ϩᚆપϯϐǴωள‫ډ‬ϯӝ‫ނ‬. 19Ǵՠࢂౢ౗КႣයٰளե(yield 12.4 %)Ƕ 3.3.1.3. 2'-Fluoro-6,7-methylenedioxy-2-phenyl-4-(O-N,Ndimethylethylenediaminyl carbonyl)quinoline (23)ϐӝԋ Scheme 9 O Cl3CO. OCCl3. +. 20. N. H 2N. O. NEt3(cat.) CH2Cl2, 0к~rt Cl. 21. N. N H. 22 O. O O Cl. +. N H. N. O O. F N H. O. pyridine 140-145 к. N H. O O. N. N F. 22. 11a. 23. ӵ Scheme 924 ‫܌‬ҢǴ๱‫ޣ‬ќѦΨஒ N,N-dimethylethyl-. enediamine (21)Ӄᆶ triphosgene (20)ϸᔈǴ٬ 21 ่ᄬύ‫ޑ‬΋ 32.

(40) ભේ΢଺ carbonyl chloride ‫ڗޑ‬жԶள‫ ډ‬N,N-dimethyl-. ethylenediaminyl chloride (22)ǹௗ๱ϯӝ‫ ނ‬22 ᆶ 11a ӧ pyridine ྽ᡵϷྋ൞‫ޑ‬చҹΠ຾Չ‫ڗ‬жϸᔈԶள‫؃܌ډ‬ϯӝ ‫ ނ‬4-N,N-dimethylethylenediaminyl-2'-fluoro-6,7-. (methylenedioxy)-2-phenyl-4-quinolone (23)Ƕ ӕኬӦǴϯӝ‫ ނ‬23 ‫ޑ‬ӝԋΨӃ჋၂ Scheme 7 ‫ޑ‬ϸᔈచ ҹǴࠅ҂ԖႣයϸᔈౢғǴӢԜ‫ׯ‬௦Ҕ Scheme 8 ‫ޑ‬ϸᔈచ ҹӝԋр 23Ǵౢ౗ΨόӵႣයٰளଯ (yield 10.5 %)Ƕ ϯӝ‫ ނ‬23 ‫่ޑ‬ᄬ᠘‫ۓ‬Ǻ 1. H-NMR (DMSO-d6Ǵ200 MHz) δ (ppm) (კ 26-1)Ǻ8.08-7.99 (1. H, m, H-4')Ǵ7.63 (1 H, d, J = 2.1 Hz, H-6')Ǵ7.49 (1 H, s, H-5)Ǵ 7.42-7.29 (1 H, m, H-5')Ǵ7.26-7.22 (1 H, m, H-3)Ǵ7.19-7.09 (2 H, m, H-3', H-8)Ǵ6.10 (2 H, s, CH2)Ǵ3.62-3.38 (4 H, m, H-2'', H-3'')Ǵ1.23 (6 H, t, J = 7.1 Hz, NCH3)Ǵ0.86 (1 H, br s, NH)ǹԜ ϯӝ‫ނ‬ϐNMRణ᛼ᡉҢణኧᆶႣය࣬಄ӝǴЪӧ੝ቻૻဦೀ ҭև౜҅ዴ‫ޑ‬ణኧᆶଽӝ߄౜Ƕ 13. C-NMR (DMSO-d6Ǵ50 MHz) δ (ppm) (კ 26-2)Ǻ152.7Ǵ. 151.2Ǵ148.3Ǵ131.3Ǵ130.7Ǵ130.5Ǵ124.5Ǵ118.6Ǵ116.37Ǵ 115.9Ǵ113.1Ǵ112.9Ǵ106.1Ǵ101.9Ǵ96.9Ǵ42.6Ǵ42.3Ǵ29.7Ǵ 29.7Ǵ14.5Ǵ13.3ǹҁϯӝ‫ނ‬ϐᅹ᛼ᡉҢϐᅹኧᆶႣය࣬಄ӝǶ. 33.

(41) 3.3.1.4. 2'-Fluoro-6,7-methylenedioxy-2-phenyl-4(O-4-piperidinopiperidinecarbonyl)quinoline (26)ϐӝԋ Scheme 10. N. NH. Cl. O + Cl. 24. O. O Cl Cl. N. N. benzene, <10 к. Cl. 25 O O. X. NaH, DMF, 50 к. O. N. N. F. O. N. 26 ๱‫ޣ‬ќѦ჋၂ӧ 11a ‫ޑ‬ಃ 4 Տ࿼଺ 4-piperidino-. piperidinecarbonyl ୷ი‫ڗޑ‬жǴӵ Scheme 1024,25 ‫܌‬ҢǴ२Ӄ ஒ 4-piperidinopiperidine (24)ᆶ trichloromethyl chloroformate. (25)ӧ benzene ྽ྋ൞ǵλ‫ ܭ‬10 ʚ‫ޑ‬ᕉნΠ຾Չ‫ڗ‬жϸᔈǴ Ӄ‫׎‬ԋϯӝ‫ ނ‬4-piperidinopiperidinecarbonyl chlorideǴௗ๱ᆶ. 11a ӧ DMF ྽ྋ൞ǵNaH ྽ᡵǵྕࡋ௓‫ڋ‬җ࠻ྕ໒‫ۈ‬ӛ΢ уྕǴ٠ᢀჸϸᔈǶ ࡐᒪᏬǴҁჴᡍ٠҂ԖႣය่݀ౢғǹӢԜ๱‫ޣ‬অ‫ׯ‬Α ϸᔈచҹǴӵ Scheme 1116,23 ‫܌‬ҢǺ 34.

(42) Scheme 11. O. O N. NH + Cl CO 3. 24. N OCCl3 benzene, <10 к. N. Cl. 25 O O. X. NaH, DMF, 50 к. O. N. N. F. O. N. 26 ӧԜ๱‫ޣ‬ஒಃ΋‫؁‬ᡯ(a)‫ׯ‬௦ᆶ Scheme 9 ࣬ӕ‫ޑ‬ϸᔈచ ҹǺஒ 24 ᆶ triphosgene (27)ӧ dichloromethane ྽ྋ൞ǵӇ ੎ϸᔈచҹΠ຾Չ‫ڗ‬жள‫ ډ‬4-piperidinopiperidinecarbonyl. chlorideǹԶಃΒ‫؁‬ᡯ(b)߾ࢂஒϸᔈྕࡋ۳΢ፓ᏾Կ 130 ʚǴ ٠ᢀჸϸᔈ‫ޑ‬຾ՉǶ่݀ࠅзΓѨఈǴӢԜ๱‫ޣ‬ஒಃΒ‫؁‬ᡯ ύ‫ޑ‬ྋ൞‫׳‬ඤԋҁ‫ي‬஥Ԗᡵ‫ޑ܄‬ଯ‫ݦ‬ᗺྋ൞ pyridineǴ٠٬ у዗Կ଑ࢬ‫ޑ‬చҹΠ຾Չϸᔈǹ‫؂‬႖ 1 hr ᔠෳ΋ԛϸᔈ่ ݀Ǵӧϸᔈ 10 hr ϐࡕǴϝฅؒԖၨܴᡉЪ౦‫ ܭ‬11a ‫ޑ‬Ьᗺ ౢғǶ ӧҁϸᔈǴӢࣁ benzene ‫ڀ‬Ԗၨεࢥ‫܄‬Ъόܰ‫ڗ‬ளǴࡺ ‫ׯ‬Ҕ dichloromethane ࣁྋ൞ǵtriethylamine ࣁ໽ϯᏊǵӇ੎ 35.

(43) ‫ޑ‬ϸᔈచҹǴ၀‫ݙ‬ཀ‫ࢂޑ‬బу၂Ꮚ‫ޑ‬໩‫ׇ‬ǺӢࣁ triethylamine ‫ޑ‬фҔࢂઇᚯ triphosgeneǴ٬ౢғ phosgene ᆶ 24 ϸᔈǹ‫܌‬ аᔈ၀а triethylamineǵ 24ǵdichloromethane ‫ޑ‬షӝన጗ᄌ ᅀуΕ triphosgene ᆶ dichloromethane ‫ޑ‬షӝనύǹ߻Ўύ‫܌‬ ග‫ޑډ‬ϯӝ‫ ނ‬4-piperidinopiperidinecarbonyl chloride Ӣࣁό ᛙ‫ۓ‬Ǵཱུ৒ܰዊှǴࡺ๱‫ޣ‬٠҂ஒ‫ڗځ‬рբ่ᄬ᠘‫ۓ‬Ƕ. 36.

(44) 3.3.2. 2FMPQ ϐ 4-acetic acid ़ғ‫ނ‬ϐӝԋ ़ғ‫ނ‬ϐӝԋ 3.3.2.1. 2'-Fluoro-6,7-methylenedioxy-2-phenyl-4-(O-acetic acid)quinoline (30)ϐӝԋ Scheme 12 OEt O O O. O F. O. Cl. N H. Et. O. O. O. NaH DMF, 50 к. O. N F. 11a. 28. 29 OH. OEt. O. O O O. NaOH(aq.). N. O. O. O. O. N F. F. 29. 30. ๱‫ޣ‬ҭ჋၂ӝԋ 11a ӧಃ 4 Տ࿼΢а acetic acid ࣁ‫ڗ‬ж ୷‫ޑ‬ϯӝ‫ ނ‬30ǴӝԋБ‫ݤ‬ӵ Scheme 1223 ‫܌‬ҢǺ11a ᆶ ethyl. chloroacetate (28)ӧ DMF ྽ྋ൞ǵNaH ྽ᡵǵྕࡋፓ௓ӧ 50 ʚǴ຾Չᙁൂ‫ڗޑ‬жϸᔈԶள‫ډ‬ϯӝ‫ ނ‬2'-fluoro-6,7-. (methylenedioxy)-2-phenyl-4-(O-ethyl acetate)quinoline (29)ǹ ϯӝ‫ ނ‬29 ࿶ၸપϯϐࡕǴҔ NaOH(aq)Нှёள‫؃܌ډ‬ϯӝ‫ނ‬. 2'-fluoro-6,7-(methylenedioxy)-2-phenyl-4-(O-acetic acid)quinoline (30)Ƕ ϯӝ‫ ނ‬30 ‫่ޑ‬ᄬ᠘‫ۓ‬Ǻ 37.

(45) IRკ᛼(კ27-1) νmax (KBr) cm-1Ǻ‫ܭ‬1616 cm-1ೀԖ(C=C)՜৖ਁ ୏֎ԏঢ়Ǵ‫ܭ‬1716 cm-1ೀԖ(C=O)՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬2895. cm-1ೀԖ(O-H)ቨε՜৖ਁ୏֎ԏঢ়Ǵ‫ܭ‬3061 cm-1ೀԖ҂Ⴋ‫ک‬ ‫ޱ‬३‫(܄‬C-H)՜৖ਁ୏֎ԏঢ়ǹ߻ॊ੝ቻࣣ಄ӝҁϯӝ‫ނ‬ӧ IR კ᛼‫߄ޑ‬౜Ƕ ፦᛼(EIMS) (კ27-2)Ǻϩηᚆηঢ়ࣁ (m/z 341.2)Ǵᆶϯӝ‫ނ‬ϩ ηԄC18H12FNO5࣬಄Ƕ 1. H-NMR (DMSO-d6Ǵ200 MHz) δ (ppm) (კ 27-3)Ǻ13.27 (1 H,. br s, COOH)Ǵ7.97-7.89 (1 H, m, H-4')Ǵ7.52-7.29 (5 H, m, H-3, H-5, H-8, H-3', H-5')Ǵ7.16 (1 H, d, J = 1.1 Hz, H-6')Ǵ6.22 (2 H, s, OCH2O)Ǵ5.02 (2 H, s, OCH2COOH)ǹԜϯӝ‫ނ‬ϐNMRణ᛼ ᡉҢణኧᆶႣය࣬಄ӝǴЪӧ੝ቻૻဦೀҭև౜҅ዴ‫ޑ‬ణኧᆶ ଽӝ߄౜Ƕ 13. C-NMR (DMSO-d6Ǵ50 MHz) δ (ppm) (კ 27-4)Ǻ169.9Ǵ. 160.08Ǵ152.4Ǵ151.4Ǵ147.9Ǵ147.2Ǵ131.6Ǵ131.5Ǵ131.3Ǵ 125.1Ǵ116.9Ǵ116.5Ǵ115.9Ǵ105.7Ǵ102.6Ǵ102.2Ǵ97.3Ǵ65.3ǹ ҁϯӝ‫ނ‬ϐᅹ᛼ᡉҢϐᅹኧᆶႣය࣬಄ӝǶ Ӣࣁϯӝ‫ ނ‬18 ᆶϯӝ‫ ނ‬16 ่ᄬԄ࣬՟Ǵࡺ๱‫ޣ‬२Ӄа. Scheme 7 ‫ޑ‬చҹ჋၂ӝԋ 19Ǵࠅ҂ள‫܌ډ‬ሡϯӝ‫ނ‬Ƕ௢ෳ ёૈࢂྕࡋό‫ى‬Ꮴठ 11a ϐಃ 4 Տ࿼΢‫਼ޑ‬চη‫ځ‬ϸᔈ‫܄‬ό. 38.

(46) ‫ى‬а٬ 18 ่ᄬύ‫ޑ‬ෛᚆηᚆѐǹᅟࡕ๱‫ޣ‬ԵቾҔ‫ڀ‬Ԗᡵ‫܄‬Ъ ‫ݦ‬ᗺ‫׳‬ଯ‫ ޑ‬pyridine ྽ྋ൞Ǵӆஒྕࡋፓ᏾Կౢғ଑ࢬǴϸ ᔈ 10 hrǴTLC ТᢀჸςԖ౦‫ ܭ‬11a ϐќ΋Ьᗺ‫ޑ‬อ‫๋ݢ‬ѦӀ ֎ԏǴӢԜӆз‫ځ‬ϸᔈ 10 hrǴՠ 11a ӧ TLC ТΠև౜‫ޑ‬ᐚ ࡋ٠คᡂ఩ǴӢԜஒϸᔈύЗ٠ϩᚆપϯϐǴωள‫ډ‬ϯӝ‫ނ‬. 19Ǵՠࢂౢ౗КႣයٰளե(yield 12.4 %)Ƕ. 39.

(47) 3.3.3. 2FMPQ ϐ 4-carbonate ़ғ‫ނ‬ϐӝԋ ़ғ‫ނ‬ϐӝԋ 3.3.3.1. 2'-Fluoro-6,7-methylenedioxy-2-phenyl-4(O-N,N-dimethylethanolaminecarbonyl)quinoline (32)ϐӝԋ Scheme 13 O N. OH. NEt3 (cat.). + Cl CO 3. OCCl3. 31. O N. CH2Cl2, ice bath. O Cl. 27 O O. X NaH, DMF, 130 к. O O. N. O F. N. 32 ӵ Scheme 1323,25 ‫܌‬ҢǴ Ǵ๱‫ޣ‬ҭ჋၂ӧ 11a ‫ޑ‬ಃ 4 Տ࿼ ΢଺ carbonate ‫ڗޑ‬жǴ२Ӄஒ N,N-dimethyl ethanolamine (31) ᆶ triphosgene (27)ӧ dichloromethane ྽ྋ൞ǵӇ੎ϸᔈచҹ Π (a)຾Չ‫ڗ‬жϸᔈள‫ ډ‬N,N-dimethylethanolaminecarbonyl. chlorideǹௗ๱ӧ DMF ྽ྋ൞ǵNaH ྽ᡵǵྕࡋ௓‫ڋ‬ӧ 130 ʚ ‫ޑ‬ϸᔈచҹΠ(b)Ǵ၂๱ӝԋϯӝ‫ ނ‬2'-fluoro-6,7-. (methylenedioxy)-2-phenyl-4-(O-N,N-dimethylethanolaminecar bonyl)quinoline (32)Ƕ ҁϸᔈҭόӵႣය‫่݀ޑ‬Ǵӧϸᔈ 10 hr ϐࡕǴ TLC Т 40.

(48) ΢‫ޑ‬চ਑ᗺ(11a)ϝฅࢂЬᗺǴؒԖ‫ځ‬Ꭹཥ‫ޑ‬ЬᗺౢғǶ ӢԜ๱‫ޣ‬ӆஒಃΒ‫؁‬ᡯ‫ޑ‬ྋ൞‫׳‬ඤԋଯ‫ݦ‬ᗺ‫ޑ‬. pyridineǴ٠ஒྕࡋуଯԿౢғ଑ࢬǴёெϸᔈ٩ฅค୏‫ܭ‬ ૱Ƕ௢ෳёૈࢂӢࣁ carbonate ৒ܰᘐ຋Ǵ٬ளౢ‫ނ‬όӼ‫ۓ‬Ǵ ࡺ๱‫ޣ‬ӧख़ፄჴᡍ‫ޑ‬ၸำύ‫ׯ‬ԋ‫؂‬႖ 10 min ൩а TLC Тբ ଓᙫᔠෳǴՠϝคҺՖϸᔈǶ. 41.

(49) 3.3.4. 2FMPQ ϐ 4-amines ़ғ‫ނ‬ϐӝԋ ़ғ‫ނ‬ϐӝԋ ๱‫ޣ‬჋၂ஒ 11a ಃ 4 Տ࿼‫ ޑ‬ketone ୷იаᕉ‫่ރ‬ᄬ‫ޑ‬Β ભ amines ଺‫ڗ‬жǴ΋Бय़‫׆‬ఈᙖҗ bioisosterism ‫ׯޑ‬ᡂ௖૸ ‫܄ࢲځ‬ᆶ่ᄬ‫ޑ‬ᜢ߯Ǵќ΋Бय़ǴΨ‫׆‬ఈճҔΟભữᜪࢎᄬǴ аቚуԜᜪϯӝ‫ނ‬ϐНྋ‫܄‬Ǵ၁ಒӝԋБ‫ݤ‬Ϸ௶ॊӵΠǺ. 3.3.4.1. 2'-Fluoro-6,7-methylenedioxy-2-phenyl-4(pyrrolidine)quinoline (35)ϐӝԋ Scheme 14 O O. Cl F. O. N H. POCl3. O. 90-100 к. O. 11a. 33. O. H N. O O. O. phenol,140-145 к. Cl. F N. O. F. F N. 34. N H N. 33. N 110 к. O O. F N. 35. 42.

(50) ӵ Scheme 1426,27 ‫܌‬ҢǴ๱‫ޣ‬Ӄஒ 11a ᆶ phosphoryl. chloride(POCl3)ϸᔈǴ٬ಃ 4 Տ࿼΢‫ ޑ‬ketone ୷ი຾Չ chlorinationǴள‫ډ‬ϯӝ‫ ނ‬33ǶᒿࡕǴ๱‫ޣ‬ஒ 33 ᆶ pyrrolidine ӧ phenol ࣁྋ൞ǵྕࡋፓ௓Կ 140-145 ʚ‫ޑ‬ϸᔈచҹΠᠳ ܏Ǵයఈёа໩ճ຾Չ‫ڗ‬жϸᔈǴӝԋ 2'-fluoro-. 6,7-methylenedioxy-2-phenyl-4-(pyrrolidine)quinoline (35)ǹჴ ߾όฅǴϸᔈ࿶ၸ 5 hr ϐࡕǴ TLC Т΢ౢғ౦‫ܭ‬চ਑ 33 ‫ޑ‬ ќ΋ЬᗺǴࡺ๱‫ޣ‬ஒϸᔈ଺પϯǴ࿶ၸ่ᄬ᠘‫ۓ‬ϐࡕǴӧ 33 ಃ 4 Տ࿼ௗ΢‫ڗޑ‬ж୷იࢂҁ‫؁‬ᡯύ٬Ҕ‫ޑ‬ྋ൞ phenolǴள ‫ډ‬Α 2'-fluoro-6,7-methylenedioxy-2-phenyl-4-(phenol). quinoline (34)ǴԶόࢂচӃ‫܌‬Ⴃයள‫ޑډ‬ϯӝ‫ ނ‬35ǹ௢ෳӢ ࣁ phenol ࣁྋ൞ǴӢԜ྽ໆኧᇻКϸᔈ၂Ꮚ pryyolidine ٰள ӭǴӆу΢ phenol ୷იύ֖Ԗ਼চηǴ਼চη஥Ԗ‫ޑ‬҂ӅҔ ႝηჹ࿶ၸёа྽ԋ১ᡵ‫ ޑ‬pyrrolidine բҔࡕϸԶ٬‫ځ‬ᒃਡ ‫܄‬εε‫ޑ‬ගϲΑǴ‫܌‬аӧԜϸᔈ຾ՉਔǴphenol ஒ 33 ΢‫ޑ‬ᚆ ѐ୷ (ෛᚆη )‫ڗ‬жǴԶനಖӝԋΑ 34Ƕ ӢԜǴ๱‫ޣ‬ӧϸᔈచҹ΢଺Αঅ҅Ǵஒ 33 ‫ޔ‬ௗа. pyrrolidine ྽১ᡵǵྋ൞Ψ྽ԋ၂ᏊǴྕࡋ߾ࢂፓ௓Կౢғ ଑ࢬٰ຾Չ‫ڗ‬жϸᔈǹϸᔈ࿶ၸ 5 hrǴԖܴᡉЪ౦‫ ܭ‬33 ‫ޑ‬Ь ᗺӧ TLC Т‫ޑ‬อ‫๋ݢ‬ѦӀΠᢀჸ‫ډ‬ǴஒϸᔈપϯϐࡕǴനಖ ள‫ډ‬ϯӝ‫ ނ‬35Ƕ. 43.

(51) 3.3.4.2. 2'-Fluoro-6,7-methylenedioxy-2-phenyl-4(4-methylpiperazine)quinoline (36)ϐӝԋ Scheme 15 O O. Cl POCl3. O. 90-100 к. O. F. O. N H. 11a. O O. N. 33. N. NH. phenol,140-145 к. Cl. F. O O O. F. F N. 34. N N. NH. N. 33 140-145 к. N O O. F N. 36. ӵ Scheme 1526,27,28 ‫܌‬ҢǴ๱‫ޣ‬ҭӃஒ 11a ‫ޑ‬ಃ 4 Տ. ketone ୷ი chlorination ள‫ډ‬ϯӝ‫ ނ‬33ǶᒿࡕǴ๱‫ޣ‬ஒ 33 ᆶ 1-methylpiperazine ӧ phenol ࣁྋ൞ǵྕࡋፓ௓Կ 140-145 ʚ ‫ޑ‬ϸᔈచҹΠᠳ܏Ǵයఈёа໩ճ຾Չ‫ڗ‬жϸᔈǴӝԋ. 2'-fluoro-6,7-methylenedioxy-2-phenyl-4-(4-methylpiperazine) quinoline (36)ǹჴ߾όฅǴϸᔈ࿶ၸ 5 hr ϐࡕǴTLC Т΢ౢ ғ౦‫ܭ‬চ਑ 33 ‫ޑ‬ќ΋ЬᗺǴࡺ๱‫ޣ‬ஒϸᔈ଺પϯǴ࿶ၸ่ᄬ 44.

(52) ᠘‫ۓ‬ϐࡕǴӧ 33 ಃ 4 Տ࿼ௗ΢‫ڗޑ‬ж୷იࢂҁ‫؁‬ᡯύ٬Ҕ‫ޑ‬ ྋ൞ phenolǴள‫ډ‬Α 2'-fluoro-6,7-methylenedioxy-2-phenyl-. 4-(phenol)quinoline (34)ǴԶόࢂচӃ‫܌‬Ⴃයள‫ޑډ‬ϯӝ‫ނ‬ 36ǹ௢ෳӢࣁ phenol ࣁྋ൞ǴӢԜ྽ໆኧᇻКϸᔈ၂Ꮚ 1-methylpiperazine ٰளӭǴӆу΢ phenol ୷იύ֖Ԗ਼চ ηǴ਼চη஥Ԗ‫ޑ‬҂ӅҔႝηჹ࿶ၸёа྽ԋ১ᡵ‫ޑ‬. 1-methylpiperazine բҔࡕϸԶ٬‫ځ‬ᒃਡ‫܄‬εε‫ޑ‬ගϲΑǴ‫܌‬ аӧԜϸᔈ຾ՉਔǴphenol ஒ 33 ΢‫ޑ‬ᚆѐ୷(ෛᚆη )‫ڗ‬жǴ ԶനಖӝԋΑ 34Ƕ ӢԜǴ๱‫ޣ‬ӧϸᔈచҹ΢଺Αঅ҅Ǵஒ 33 ‫ޔ‬ௗа. 1-methylpiperazine ྽১ᡵǵྋ൞Ψ྽ԋ၂Ꮚǵྕࡋ߾ࢂፓ௓ Կౢғ଑ࢬٰ຾Չ‫ڗ‬жϸᔈǹϸᔈ࿶ၸ 5 hrǴԖܴᡉЪ౦‫ܭ‬. 33 ‫ޑ‬Ьᗺӧ TLC Т‫ޑ‬อ‫๋ݢ‬ѦӀΠᢀჸ‫ډ‬Ǵஒϸᔈપϯϐ ࡕǴനಖள‫ډ‬ϯӝ‫ ނ‬36Ƕ. 45.

(53) 3.4. 6,7-Methylenedioxy-2-(2,3,4-substituted phenyl)4-quinolones ࣬ᜢϐ ࣬ᜢϐႝတϩηኳᔕ 3.4.1. ႝတϩηኳᔕ(molecular modeling)ϐཷॊ ႝတϩηኳᔕ‫ೌמ‬ӧ߈ԃٰς࿶೴ᅌ೏ᔈҔӧ೚ӭ஑ ཰ሦୱǴႽࢂ‫ނ‬౛Ꮲ‫ޑ‬ႝတኳᔕϩηၮ୏ǵғ‫מࣽނ‬Бय़ϩ ηғ‫ނ‬Ꮲǵೈқ፦ᡏᏢаϷϩη୏ᄊኳᔕ೿ࢂаԜ‫ٰೌמ‬բ ࣁਥ୷Ǵӆ຾΋‫׳଺؁‬ుΕӦ௖૸ᆶࣴ‫ز‬Ƕႝတϩηኳᔕࢂ ΋ᅿ่ӝႝတࣽ‫מ‬ᆶϩη่ᄬ‫ೌמޑ‬ǴճҔኳᔕλϩη่ᄬ ӧ࣬ᜢբҔ೽Տ‫ޑ‬༾ᢀ߄౜Ǵٰ௢ෳ౛ፕ΢၀ϩηჴሞၮբ ௃‫׎‬ǹԶၟ‫ॺך‬৲৲࣬ᜢ‫ޑ‬ᛰ‫ނ‬ӝԋᆶ೛ीӧЇΕԜᅿ‫ೌמ‬ ϐࡕǴନΑεεफ़ե࣬ᜢࣴ‫ز‬ԋҁǵуೲཥӝԋᛰ‫ޑނ‬ᑔᒧǴ аය‫׳‬Ԗਏ౗Ӧ๱Ћ຾Չཥᑉᛰ‫ނ‬ϐӝԋᆶ೛ीǶ!. 3.4.2. ࣴ‫ز‬࿶ၸ ਥᏵЎ᝘ள‫ ޕ‬16Ǵ2-PQ ᜪϯӝ‫ނ‬ԖᡏѦᛰ౛၂ᡍࢲ‫܄‬ ‫ޣ‬Ǵӧ࿶ၸऍ୯ NCI (National Cancer Institute)а patterns of. differential cytotoxicity toward human tumor cell lines ‫ޑ‬БԄ ዴᇡǴҁᜪϯӝ‫ނ‬ឦ‫לܭ‬ಒझԖํϩ຋ᇙᏊ(antimitotic. agents)Ǵᛰ౛բҔϐኳԄᆶ colchicine ᜪ՟ࠅόᅰ࣬ӕǹӧԜ ЇҔЎ᝘ύᜢ‫ܭ‬ҁᜪϯӝ‫ޑނ‬ᛰ౛ၗ਑ (Table 2)Ǻᗨฅҁᜪ ϯӝ‫ނ‬ӧ ITP (inhibition of tubulin polymerization)‫ޑ‬ᛰ౛၂ᡍ ύᡉҢрᓬຫ‫ ޑ‬IC50 ॶǴόၸࠅ‫ ځ‬ITP ॶࠅόӵႣයᆶ 46.

(54) ICB(inhibition of colchicine binding)ॶև౜҅࣬ᜢ‫܄‬Ƕ Table 2. 2-PQ ᜪϯӝ‫ނ‬ϐ ITP ॶᆶ ICB ॶӈ߄ O O. R1. O. R2. N H. R3. 11a-j a:R1=F, R2=H, R3= H b: R1= Cl, R2= H, R3= H c: R1= OCH3, R2= H, R3= H d: R1= H, R2=F, R3= H e: R1= H, R2=Cl, R3= H. f: R1= H, R2= OCH3, R3= H g: R1= H, R2= H, R3=F h: R1= H, R2= H, R3=Cl i: R1= H, R2= H, R3= OCH3 j: R1= H, R2= H, R3= H. 11a. ITPa IC50(μM) ± SD 0.85 ± 0.1. ICBb (% inhibition) 37 ± 3. 11b. 0.89 ± 0.1. 24 ± 4. 11c. 14 ± 0.5. -. 11d. 0.53 ± 0.1. 51 ± 3. 11e. 0.37 ± 0.03. 45 ± 7. 11f. 0.57 ± 0.1. 39 ± 8. 11g. -. -. 11h. -. -. 11i. > 40. -. CA-4. 0.53 ± 0.05. 94 ± 2. colchicine. 0.8 ± 0.07. -. Compd. a. ITP = inhibition of tubulin polymerization. b ICB = inhibition. of colchicine binding. 47.

(55) ӢԜǴ๱‫ޣ‬టճҔႝတኳᔕ‫س‬಍ஒ΋‫س‬ӈӝԋрϐ. 6,7-methylenedioxy- 2-(2,3,4-substituted phenyl)-4-quinolones ᆶ΋‫ڀ‬Ԗ colchicine Ϸ stathmin-like ่ӝ೽Տ‫ ޑ‬tubulin ೈқ ፦຾Չ docking29Ǵ٠຾΋‫؁‬௖૸Ԝ΋‫س‬ӈϯӝ‫ނ‬ᆶ. colchicineǵcombretastatin A-4 ӧᆶ tubulin ่ӝਔ‫ޑ‬ৡ౦ࣁ ՖǶ ਥᏵୖԵЎ᝘ள‫ ޕ‬30Ǵӧ microtubule ຾Չ assembly а Ϸ dynamic instability ਔǴሡ౐ੋ‫ ډ‬tubulin-GTP dimerǵ. tubulin-GDP dimer ‫׎ޑ‬ԋᆶϩှǴΠБࣁ microtubule dynamic instability ϐᙁკ(Fig. 6)Ǻ. Fig. 6 Microtubule Dynamic Instability ӵ Fig. 6 ‫܌‬ҢǴӧ tubulin ຾Չ growth phase ਔǴ. GTP-tubulin dimers ཮΋΋‫ ܭ‬tubulin ҃ᆄௗ΢Զቚу tubulin. 48.

(56) ᆫӝϐߏࡋǴϸϐǴ྽ tubulin ຾Չ shortening phase ਔǴGTP ཮ϩှ٠ញ‫ܫ‬р phosphate ᙯᡂԋࣁ GDPǴGTP-tubulin dimers ߾‫׎‬ԋ GDP-tubulin dimersǴ٠೴΋Ծᆫӝϐ tubulin ಥᚆǴ ௗ๱ஒ GDP ಥନǴ฻ࡑख़ཥᆶ GTP ่ӝ‫׎‬ԋ GTP-tubulin. dimerǴа຾ՉΠ΋ԛ tubulin ϐ growth phaseǶ २ӃǴ๱‫ޣ‬ᒧҔϐႝတኳᔕ‫س‬಍ࣁ Discovery Studio. molecular modeling (D.S. modeling)Δҁ‫س‬಍ࣁ΋ 3D ҥᡏ୏ฝ ೬ᡏǴЬाфૈࣁ೸ၸ ligand ᆶ protein և౜р‫ ޑ‬3D ҥᡏ୏ ฝኳԄٰᢀჸ ligand ᆶ protein ϐ໔‫࣬ޑ‬ϕբҔ௃‫׎‬Ƕ ๱‫ޣ‬ᒧҔϐೈқ፦ࣁ PDB (protein data bank)‫س‬಍ύǴж ဦࣁ 1SA0 ϐ่ᄬǴ่ᄬࣁ tubulin ᆶ colchicine analogous ϐ. co-crystal(Ӆ่඲)ǴЪς࿶ၸ X-ray ‫ۓ‬рዴϪ่ᄬǴresolution ࣁ 3.58 ÅǶӧԜ co-crystal ่ᄬύǴӅԖ 8 ঁ ligands ᢃ൪ӧ ‫ځ‬ύǴϩձࢂ megnesium ion(Mg 2+)‫ٿ‬ೀǵ GTP(guanosine-. 5'-triphosphate)‫ٿ‬ೀǵGDP (guanosine-5'-diphosphate)‫ٿ‬ೀаϷ colchicine analogous (2-mercapto-N-[1,2,3,10-tetramethoxy9-oxo-5,6,7,9- tetrahydro-benzo[A]heptalen-7-yl]acetamide)‫ٿ‬ ೀǴࡺ๱‫ޣ‬ᒧҔ ligands ύ՞Ᏽᡏᑈၨᚳε‫ޣ‬Ǵஒ‫ځ‬ᆶ tubulin ϐ่ӝ೽Տаႝတኳᔕ‫س‬಍‫ۓ‬ကࣁҁԛ٬Ҕϐ binding. sitesǴϩձԖ GTP 600ǵGTP 601ǵGDP 602ǵGDP 603ǵCN2 700ǵCN2 701 ฻ 6 ೀ binding sitesǶ. 49.

(57) ᅟࡕǴ๱‫ޣ‬ஒҁ‫س‬಍ϐ forcefield ೛‫ ࣁۓ‬Dreiding ኳԄǴ ٠٬ట docking ϐϯӝ‫ૈ଺ނ‬ໆനλϯǹ࣬ᜢ೛‫ࡕ״่ۓ‬Ǵ ϯӝ‫ ނ‬11a-j ϩձᆶ߻ॊ 6 ೀ‫ۓ‬ကϐ binding sites ຾Չ. dockingǴ‫ঁځ‬ձϐ่݀ፕॊӵΠǺ 3.4.3. ࣴ‫่݀ز‬ᆶ૸ፕ ࣴ‫่݀ز‬ᆶ૸ፕ 3.4.3.1. 2'-Fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (11a)ϐϩηኳᔕ. O. 6. O 7. 5. 8. O 4 N. 3. F. 2 1'. 2' 3'. 1. H. 6'. 4' 5'. 11a 3.4.3.1.1. 11a ‫ ܭ‬GDP 602 ϐ docking ႝတ຾Չ 11a ᆶ tubulin ϐ GDP 602 binding site. docking ่‫ࡕ״‬Ǵ๱‫ޣ‬җኳᔕ‫س‬಍ύᑔᒧр 10 ฽ၗ਑Ǵࢂа dock-score ଯե໩‫ׇ‬௨ӈԶԋǴ‫࣬ځ‬ᜢၗૻӵ Table 3-1Ǻ. 50.

(58) Table 3-1. 11a ‫ ܭ‬GDP 602 ϐ binding ၗૻ Ligand Dock Rank. Initial Energy Forcefield. score. HB internal. Energy. Number energy. 1. 53.057 59.732 Dreiding 59.732 -3.659. 1. 2. 49.34 59.732 Dreiding 59.732. -3.71. 1. 3. 48.911 59.732 Dreiding 59.732 -3.712. 1. 4. 48.703 59.732 Dreiding 59.732 -3.712. 2. 5. 48.536 59.732 Dreiding 59.732 -3.541. 2. 6. 48.459 59.732 Dreiding 59.732 -3.687. 2. 7. 48.201 59.732 Dreiding 59.732 -3.613. 2. 8. 48.033 59.732 Dreiding 59.732 -3.679. 2. 9. 47.96 59.732 Dreiding 59.732 -3.132. 2. 10. 47.921 59.732 Dreiding 59.732 -3.702. 1. ๱‫ޣ‬టஒ docking ϐ၁௃კҢ‫ܭ‬ԜǴਥᏵϩηኳᔕ‫س‬ ಍ύǴϩηᆶ༾ᆅೈқ፦ϐణᗖբҔΚኧҞനӭࣁᓬӃǴЪ Ӣࣁ dock score ௨Ӝಃ 4 Կಃ 9 ‫่ޑ‬ӝࠠᄊ࣬ӕǴࡺ๱‫ޣ‬ᒧ ‫ڗ‬Α dock score 48.703 Տۚಃ 4 ϐϩη (аಉᡏ኱Ң‫ٯࣁ)ޣ‬ឍ ॊϐ (კ A-1)Ƕ 51.

(59) კ A-1. 11a ‫ ܭ‬tubulin ϐ GDP 602 binding site ణᗖբҔ௃‫׎‬ җკ A-1 ‫܌‬Ңள‫ޕ‬Ǵ11a ‫ ܭ‬tubulin ϐ GDP 602 binding. site аణᗖ่ӝࣁЬǴϩձа҆ਡಃ 1 Տ࿼΢ϐణচηᆶಃ 6 Տ࿼΢ϐ਼চηᆶ tubulin ౢғϩη໔‫ޑ‬ణᗖբҔΚǴᆶ 11a ่ӝϐೈқ፦೽ՏǴϩձࢂữ୷ለ‫ׇ‬ӈಃ 11 ‫ ޑ‬Glutamine. (GLN)Ϸữ୷ለ‫ׇ‬ӈಃ 206 ‫ ޑ‬Asparagine(ASN)Ƕ 3.4.3.1.2. 11a ‫ ܭ‬GDP 603 ϐ docking ႝတ຾Չ 11a ᆶ tubulin ϐ GDP 603 binding site. docking ่‫ࡕ״‬Ǵ๱‫ޣ‬җኳᔕ‫س‬಍ύᑔᒧр 10 ฽ၗ਑Ǵࢂа dock-score ଯե໩‫ׇ‬௨ӈԶԋǴ‫࣬ځ‬ᜢၗૻӵ Table 3-2Ǻ. 52.

(60) Table 3-2. 11a ‫ ܭ‬GDP 603 ϐ binding ၗૻ Ligand Dock Rank. Initial Energy Forcefield. score. HB internal. Energy. number energy. 1. 47.443 59.732. Dreiding 59.732. -3.541. 2. 2. 44.574 59.732. Dreiding 59.732. -3.713. 2. 3. 44.257 59.732. Dreiding 59.732. -2.581. 2. 4. 44.217 59.732. Dreiding 59.732. -3.714. 2. 5. 44.126 59.732. Dreiding 59.732. -2.468. 2. 6. 44.108 59.732. Dreiding 59.732. -3.67. 2. 7. 44.094 59.732. Dreiding 59.732. -3.714. 2. 8. 43.863 59.732. Dreiding 59.732. -2.269. 2. 9. 43.732 59.732. Dreiding 59.732. -3.71. 1. 10. 43.676 59.732. Dreiding 59.732. -2.232. 2. ๱‫ޣ‬టஒ docking ϐ၁௃კҢ‫ܭ‬ԜǴਥᏵϩηኳᔕ‫س‬ ಍ύǴϩηᆶ༾ᆅೈқ፦ϐణᗖբҔΚኧҞനӭࣁᓬӃǴЪ Ӣࣁ dock score ௨Ӝಃ 1 Կಃ 8 аϷಃ 10 ‫่ޑ‬ӝࠠᄊ࣬ӕǴ ᒧ‫ڗ‬Α dock score 47.443 Տۚಃ 1 ϐϩη (аಉᡏ኱Ң‫ٯࣁ) ޣ‬ ឍॊϐ(კ A-2) 53.

(61) კ A-2. 11a ‫ ܭ‬tubulin ϐ GDP 603 binding site ణᗖբҔ௃‫׎‬ җკ A-2 ‫܌‬Ңள‫ޕ‬Ǵ11a ‫ ܭ‬tubulin ϐ GDP 603 binding. site аణᗖ่ӝࣁЬǴϩձа҆ਡಃ 4 Տ࿼΢ϐ਼চηᆶಃ 6 Տ࿼΢ϐ਼চηᆶ tubulin ౢғϩη໔‫ޑ‬ణᗖբҔΚǴᆶ 11a ่ӝϐೈқ፦೽ՏǴϩձࢂữ୷ለ‫ׇ‬ӈಃ 11 ‫ ޑ‬Glutamine. (GLN)Ϸữ୷ለ‫ׇ‬ӈಃ 206 ‫ ޑ‬Asparagine(ASN)Ƕ 3.4.3.2. 2'-Chloro-6,7-methylenedioxy-2-phenyl-4-quinolone (11b)ϐϩηኳᔕ. O. 6. O 7. 5. 8. O 4 N. 3. Cl 2 1' 2'. 1. H. 4'. 6' 5'. 11b. 54. 3'.

(62) 3.4.3.2.1. 11b ‫ ܭ‬GDP 602 ϐ docking ႝတ຾Չ 11b ᆶ tubulin ϐ GDP 602 binding site. docking ่‫ࡕ״‬Ǵ๱‫ޣ‬җኳᔕ‫س‬಍ύᑔᒧр 10 ฽ၗ਑Ǵࢂа dock-score ଯե໩‫ׇ‬௨ӈԶԋǴ‫࣬ځ‬ᜢၗૻӵ Table 4-1Ǻ Table 4-1. 11b ‫ ܭ‬GDP 602 ϐ binding ၗૻ Ligand Dock Rank. Initial Energy Forcefield. score. HB internal. Energy. number energy. 1. 53.941ʳ 56.069 Dreidingʳ 56.069. -4.026ʳ. 1ʳ. 2. 52.344ʳ 56.069 Dreidingʳ 56.069. -4.355ʳ. 1ʳ. 3. 52.326ʳ 56.069 Dreidingʳ 56.069. -4.335ʳ. 1ʳ. 4. 52.162ʳ 56.069ʳ Dreidingʳ 56.069ʳ -3.693ʳ. 2ʳ. 5. 51.693ʳ 56.069 Dreidingʳ 56.069. -2.032ʳ. 2ʳ. 6. 50.976ʳ 56.069 Dreidingʳ 56.069. -4.396ʳ. 1ʳ. 7. 50.629ʳ 56.069 Dreidingʳ 56.069. -4.393ʳ. 1ʳ. 8. 50.62ʳ 56.069 Dreidingʳ 56.069. -4.171ʳ. 2ʳ. 9. 50.339ʳ 56.069ʳ Dreidingʳ 56.069ʳ -4.396ʳ. 2ʳ. 10. 50.143ʳ 56.069 Dreidingʳ 56.069. 2ʳ. 55. -1.044ʳ.

(63) ๱‫ޣ‬టஒ docking ϐ၁௃კҢ‫ܭ‬ԜǴਥᏵϩηኳᔕ‫س‬ ಍ύǴϩηᆶ༾ᆅೈқ፦ϐణᗖբҔΚኧҞനӭࣁᓬӃǴЪ Ӣࣁ dock score ௨Ӝಃ 4ǵಃ 5ǵಃ 8 аϷಃ 10 ‫่ޑ‬ӝࠠᄊ ࣬ӕǴࡺᒧ‫ڗ‬Α dock score 52.162 Տۚಃ 4 аϷ dock score. 50.339 Տۚಃ 9 ϐϩη(аಉᡏ኱Ң‫ٯࣁ)ޣ‬ឍॊϐ(კ B-1, B-2). კ B-1. 11b ‫ ܭ‬tubulin ϐ GDP 602 binding site ణᗖբҔ௃‫׎‬. (dock score 52.162 Տۚಃ 4 ‫)ޣ‬ җკ B-1 ‫܌‬Ңள‫ޕ‬Ǵ11b ‫ ܭ‬tubulin ϐ GDP 602 binding. site аణᗖ่ӝࣁЬǴϩձа҆ਡಃ 1 Տ࿼΢ϐణচηᆶಃ 4 Տ࿼΢ϐ਼চηᆶ tubulin ౢғϩη໔‫ޑ‬ణᗖբҔΚǴᆶ 11b ่ӝϐೈқ፦೽ՏǴϩձࢂữ୷ለ‫ׇ‬ӈಃ 179 ‫ ޑ‬Aspartic acid. (ASP)Ϸữ୷ለ‫ׇ‬ӈಃ 12 ‫ ޑ‬Cysteine(CYS)Ƕ. 56.

(64) კ B-2. 11b ‫ ܭ‬tubulin ϐ GDP 602 binding site ణᗖբҔ௃‫׎‬ (dock score 50.339 Տۚಃ 9 ‫)ޣ‬ җკ B-2 ‫܌‬Ңள‫ޕ‬Ǵ11b ‫ ܭ‬tubulin ϐ GDP 602 binding. site аణᗖ่ӝࣁЬǴϩձа҆ਡಃ 1 Տ࿼΢ϐణচηᆶಃ 6 Տ࿼΢ϐ਼চηᆶ tubulin ౢғϩη໔‫ޑ‬ణᗖբҔΚǴᆶ 11b ่ӝϐೈқ፦೽ՏǴϩձࢂữ୷ለ‫ׇ‬ӈಃ 11 ‫ ޑ‬Glutamine. (GLN)Ϸữ୷ለ‫ׇ‬ӈಃ 206 ‫ ޑ‬Asparagine (ASN)Ƕ 3.4.3.2.2. 11b ‫ ܭ‬GDP 603 ϐ docking ႝတ຾Չ 11b ᆶ tubulin ϐ GDP 603 binding site. docking ่‫ࡕ״‬Ǵ๱‫ޣ‬җኳᔕ‫س‬಍ύᑔᒧр 10 ฽ၗ਑Ǵࢂа dock-score ଯե໩‫ׇ‬௨ӈԶԋǴ‫࣬ځ‬ᜢၗૻӵ Table 4-2Ǻ. 57.

(65) Table 4-2. 11b ‫ ܭ‬GDP 603 ϐ binding ၗૻ Ligand Dock Rank. Initial Energy Forcefield. score. HB internal. Energy. nmber energy. 1. 51.319 56.069. Dreiding 56.069. -3.59. 2. 2. 51.117 56.069. Dreiding 56.069. -3.693. 2. 3. 50.726 56.069. Dreiding 56.069. -3.427. 2. 4. 50.027 56.069. Dreiding 56.069. -4.396. 1. 5. 48.543 56.069. Dreiding 56.069. -2.032. 2. 6. 48.303 56.069. Dreiding 56.069. -4.38. 1. 7. 48.214 56.069. Dreiding 56.069. -3.066. 2. 8. 48.111 56.069. Dreiding 56.069. -3.427. 2. 9. 48.058 56.069. Dreiding 56.069. -4.38. 1. 10. 48.038 56.069. Dreiding 56.069. -3.693. 2. ๱‫ޣ‬టஒ docking ϐ၁௃კҢ‫ܭ‬ԜǴਥᏵϩηኳᔕ‫س‬ ಍ύǴϩηᆶ༾ᆅೈқ፦ϐణᗖբҔΚኧҞനӭࣁᓬӃǴЪ Ӣࣁ dock score ௨Ӝಃ 1ǵಃ 2ǵಃ 3ǵಃ 5 ่ӝࠠᄊ࣬ӕǴ Ъ௨Ӝಃ 7ǵಃ 8 аϷಃ 10 ‫่ޑ‬ӝࠠᄊ࣬ӕǴࡺᒧ‫ڗ‬Α dock. score 51.319 Տۚಃ 1 аϷ dock score 48.214 Տۚಃ 7 ϐϩη 58.

(66) (аಉᡏ኱Ң‫ٯࣁ)ޣ‬ឍॊϐ(კ B-3, B-4). კ B-3. 11b ‫ ܭ‬tubulin ϐ GDP 603 binding site ణᗖբҔ௃‫׎‬ (dock score 51.319 Տۚಃ 1 ‫)ޣ‬ җკ B-3 ‫܌‬Ңள‫ޕ‬Ǵ11b ‫ ܭ‬tubulin ϐ GDP 603 binding. site аణᗖ่ӝࣁЬǴϩձа҆ਡಃ 1 Տ࿼΢ϐణচηᆶಃ 4 Տ࿼΢ϐ਼চηᆶ tubulin ౢғϩη໔‫ޑ‬ణᗖբҔΚǴᆶ 11b ่ӝϐೈқ፦೽ՏǴϩձࢂữ୷ለ‫ׇ‬ӈಃ 179 ‫ ޑ‬Aspartic acid. (ASP)Ϸữ୷ለ‫ׇ‬ӈಃ 12 ‫ ޑ‬Cysteine(CYS)Ƕ. 59.

(67) კ B-4. 11b ‫ ܭ‬tubulin ϐ GDP 603 binding site ణᗖբҔ௃‫׎‬. (dock score 48.214 Տۚಃ 7 ‫)ޣ‬ җკ B-4 ‫܌‬Ңள‫ޕ‬Ǵ11b ‫ ܭ‬tubulin ϐ GDP 603 binding. site аణᗖ่ӝࣁЬǴϩձа҆ਡಃ 4 Տ࿼΢ϐ਼চηᆶಃ 7 Տ࿼΢ϐ਼চηᆶ tubulin ౢғϩη໔‫ޑ‬ణᗖբҔΚǴᆶ 11b ่ӝϐೈқ፦೽ՏǴϩձࢂữ୷ለ‫ׇ‬ӈಃ 11 ‫ ޑ‬Glutamine. (GLN)Ϸữ୷ለ‫ׇ‬ӈಃ 206 ‫ ޑ‬Asparagine (ASN)Ƕ. 60.

(68) 3.4.3.3. 2'-Methoxy-6,7-methylenedioxy-2-phenyl-4quinolone (11c)ϐϩηኳᔕ. O 6 O 7. 5. 8. O 4 N1 H. 3 2. OMe 1' 2' 3' 4'. 6'. 5'. 11c 3.4.3.3.1. 11c ‫ ܭ‬GTP 600 ϐ docking ႝတ຾Չ 11c ᆶ tubulin ϐ GTP 600 binding site. docking ่‫ࡕ״‬Ǵ๱‫ޣ‬җኳᔕ‫س‬಍ύᑔᒧр 10 ฽ၗ਑Ǵࢂа dock-score ଯե໩‫ׇ‬௨ӈԶԋǴ‫࣬ځ‬ᜢၗૻӵ Table 5-1Ǻ Table 5-1. 11c ‫ ܭ‬GTP 600 ϐ binding ၗૻ Ligand Dock Rank. Initial Energy Forcefield. score. HB internal. Energy. number energy. 1. 56.974ʳ 64.586ʳ. Dreidingʳ 64.586ʳ -5.017ʳ. 1. 2. 56.682ʳ 64.586ʳ. Dreidingʳ 64.586ʳ -4.001ʳ. 1. 3. 56.483ʳ 64.586ʳ. Dreidingʳ 64.586ʳ -4.833ʳ. 1. 61.

(69) 4. 56.055ʳ 64.586ʳ. Dreidingʳ 64.586ʳ -3.997ʳ. 1. 5. 56.019ʳ 64.586ʳ. Dreidingʳ 64.586ʳ. -4.06ʳ. 1. 6. 55.894ʳ 64.586ʳ Dreidingʳ 64.586ʳ -4.994ʳ. 2. 7. 55.88ʳ 64.586ʳ. Dreidingʳ 64.586ʳ -4.473ʳ. 1. 8. 55.771ʳ 64.586ʳ. Dreidingʳ 64.586ʳ -3.949ʳ. 1. 9. 55.77ʳ 64.586ʳ. Dreidingʳ 64.586ʳ -4.957ʳ. 2. 10. 55.745ʳ 64.586ʳ. Dreidingʳ 64.586ʳ. 1. -4.08ʳ. ๱‫ޣ‬టஒ docking ϐ၁௃კҢ‫ܭ‬ԜǴਥᏵϩηኳᔕ‫س‬ ಍ύǴϩηᆶ༾ᆅೈқ፦ϐణᗖբҔΚኧҞനӭࣁᓬӃǴЪ Ӣࣁ dock score ௨Ӝಃ 6 Ϸಃ 9 ‫่ޑ‬ӝࠠᄊ࣬ӕǴࡺᒧ‫ڗ‬Α. dock score 55.894 Տۚಃ 6 ϐϩη(аಉᡏ኱Ң‫ٯࣁ)ޣ‬ឍॊϐ (კ C-1)Ƕ. კ C-1. 11c ‫ ܭ‬tubulin ϐ GTP 600 binding site ణᗖբҔ௃‫׎‬ 62.

(70) җკ C-1 ‫܌‬Ңள‫ޕ‬Ǵ11c ‫ ܭ‬tubulin ϐ GTP 600 binding. site аణᗖ่ӝࣁЬǴϩձа҆ਡಃ 4 Տ࿼΢ϐ਼চηᆶಃ 6 Տ࿼΢ϐ਼চηᆶ tubulin ౢғϩη໔‫ޑ‬ణᗖբҔΚǴᆶ 11c ่ӝϐೈқ፦೽ՏǴϩձࢂữ୷ለ‫ׇ‬ӈಃ 101 ‫ ޑ‬Asparagine. (ASN)Ϸữ୷ለ‫ׇ‬ӈಃ 254 ‫ ޑ‬Lysine (LYS)Ƕ. 3.4.3.3.2. 11c ‫ ܭ‬GTP 601 ϐ docking ႝတ຾Չ 11c ᆶ tubulin ϐ GTP 601 binding site. docking ่‫ࡕ״‬Ǵ๱‫ޣ‬җኳᔕ‫س‬಍ύᑔᒧр 10 ฽ၗ਑Ǵࢂа dock-score ଯե໩‫ׇ‬௨ӈԶԋǴ‫࣬ځ‬ᜢၗૻӵ Table 5-2 Ǻ Table 5-2. 11c ‫ ܭ‬GTP 601 ϐ binding ၗૻ Ligand Dock Rank. Initial Energy Forcefield. score. HB internal. Energy. number energy. 1. 58.339 64.586. Dreiding 64.586. -3.867. 1. 2. 56.607 64.586. Dreiding 64.586. -5.017. 1. 3. 56.473 64.586. Dreiding 64.586. -5.028. 1. 4. 56.405 64.586. Dreiding 64.586. -4.951. 1. 63.

(71) 5. 56.13 64.586. Dreiding 64.586. -4.441. 1. 6. 56.047 64.586. Dreiding 64.586. -4.61. 1. 7. 56.04 64.586. Dreiding 64.586. -4.477. 2. 8. 55.999 64.586. Dreiding 64.586. -4.665. 1. 9. 55.977 64.586. Dreiding 64.586. -5.021. 1. 10. 55.837 64.586. Dreiding 64.586. -5.058. 1. ๱‫ޣ‬టஒ docking ϐ၁௃კҢ‫ܭ‬ԜǴਥᏵϩηኳᔕ‫س‬ ಍ύǴϩηᆶ༾ᆅೈқ፦ϐణᗖբҔΚኧҞനӭࣁᓬӃǴᒧ ‫ڗ‬Α dock score 54.04 Տۚಃ 7 ϐϩη (аಉᡏ኱Ң‫ٯࣁ)ޣ‬ឍ ॊϐ (კ C-2). კ C-2. 11c ‫ ܭ‬tubulin ϐ GTP 601 binding site ణᗖբҔ௃‫׎‬ җკ C-1 ‫܌‬Ңள‫ޕ‬Ǵ11c ‫ ܭ‬tubulin ϐ GTP 600 binding. site аణᗖ่ӝࣁЬǴϩձа҆ਡಃ 4 Տ࿼΢ϐ਼চηᆶಃ 6 64.

(72) Տ࿼΢ϐ਼চηᆶ tubulin ౢғϩη໔‫ޑ‬ణᗖբҔΚǴᆶ 11c ่ӝϐೈқ፦೽ՏǴϩձࢂữ୷ለ‫ׇ‬ӈಃ 101 ‫ ޑ‬Asparagine. (ASN)Ϸữ୷ለ‫ׇ‬ӈಃ 254 ‫ ޑ‬Lysine (LYS)Ƕ. 3.4.3.3.3. 11c ‫ ܭ‬GDP 602 ϐ docking ႝတ຾Չ 11c ᆶ tubulin ϐ GDP 602 binding site. docking ่‫ࡕ״‬Ǵ๱‫ޣ‬җኳᔕ‫س‬಍ύᑔᒧр 10 ฽ၗ਑Ǵࢂа dock-score ଯե໩‫ׇ‬௨ӈԶԋǴ‫࣬ځ‬ᜢၗૻӵ Table 5-3Ǻ Table 5-3. 11c ‫ ܭ‬GDP 602 ϐ binding ၗૻ Ligand Dock Rank. Initial Energy Forcefield. score. HB internal. Energy. number energy. 1. 56.857 64.586. Dreiding 64.586. -4.69. 2. 2. 55.296 64.586. Dreiding 64.586. -4.455. 1. 3. 54.968 64.586. Dreiding 64.586. -4.898. 1. 4. 54.781 64.586. Dreiding 64.586. -4.023. 1. 5. 53.792 64.586. Dreiding 64.586. -1.493. 1. 6. 53.79 64.586. Dreiding 64.586. -4.279. 1. 65.

(73) 7. 53.023 64.586. Dreiding 64.586. -4.948. 1. 8. 52.973 64.586. Dreiding 64.586. -4.331. 1. 9. 52.882 64.586. Dreiding 64.586. -4.97. 1. 10. 52.815 64.586. Dreiding 64.586. -4.897. 1. ๱‫ޣ‬టஒ docking ϐ၁௃კҢ‫ܭ‬ԜǴਥᏵϩηኳᔕ‫س‬ ಍ύǴϩηᆶ༾ᆅೈқ፦ϐణᗖբҔΚኧҞനӭࣁᓬӃǴᒧ ‫ڗ‬Α dock score 56.857 Տۚಃ 1 ϐϩη (аಉᡏ኱Ң‫ٯࣁ)ޣ‬ឍ ॊϐ (კ C-3)Ƕ. კ C-3. 11c ‫ ܭ‬tubulin ϐ GDP 602 binding site ణᗖբҔ௃‫׎‬ җკ C-3 ‫܌‬Ңள‫ޕ‬Ǵ11c ‫ ܭ‬tubulin ϐ GDP 602 binding. 66.

(74) site аణᗖ่ӝࣁЬǴϩձа҆ਡಃ 1 Տ࿼΢ϐణচηᆶಃ 4 Տ࿼΢ϐ਼চηᆶ tubulin ౢғϩη໔‫ޑ‬ణᗖբҔΚǴᆶ 11c ่ӝϐೈқ፦೽ՏǴϩձࢂữ୷ለ‫ׇ‬ӈಃ 179 ‫ ޑ‬Aspartic acid. (ASP)Ϸữ୷ለ‫ׇ‬ӈಃ 12 ‫ ޑ‬Cysteine(CYS). 3.4.3.3.4. 11c ‫ ܭ‬GDP 603 ϐ docking ႝတ຾Չ 11c ᆶ tubulin ϐ GDP 603 binding site. docking ่‫ࡕ״‬Ǵ๱‫ޣ‬җኳᔕ‫س‬಍ύᑔᒧр 10 ฽ၗ਑Ǵࢂа dock-score ଯե໩‫ׇ‬௨ӈԶԋǴ‫࣬ځ‬ᜢၗૻӵ Table 5-4Ǻ Table 5-4. 11c ‫ ܭ‬GDP 603 ϐ binding ၗૻ Ligand Dock Rank. Initial Energy Forcefield. score. HB internal. Energy. number energy. 1. 55.37 64.586. Dreiding 64.586. -5.043. 1. 2. 52.547 64.586. Dreiding 64.586. -4.023. 2. 3. 50.783 64.586. Dreiding 64.586. -2.544. 2. 4. 50.734 64.586. Dreiding 64.586. -4.041. 1. 5. 50.135 64.586. Dreiding 64.586. -3.466. 1. 67.

(75) 6. 50.103 64.586. Dreiding 64.586. -4.094. 1. 7. 49.806 64.586. Dreiding 64.586. -4.868. 2. 8. 49.712 64.586. Dreiding 64.586. -4.933. 1. 9. 49.67 64.586. Dreiding 64.586. -4.748. 2. 10. 49.665 64.586. Dreiding 64.586. -4.333. 1. ๱‫ޣ‬టஒ docking ϐ၁௃კҢ‫ܭ‬ԜǴਥᏵϩηኳᔕ‫س‬ ಍ύǴϩηᆶ༾ᆅೈқ፦ϐణᗖբҔΚኧҞനӭࣁᓬӃǴᒧ ‫ڗ‬Α dock score 52.547 Տۚಃ 2 ϐϩη (аಉᡏ኱Ң‫ٯࣁ)ޣ‬ឍ ॊϐ (კ C-4)Ƕ. კ C-4. 11c ‫ ܭ‬tubulin ϐ GDP 603 binding site ణᗖբҔ௃‫׎‬ җკ C-4 ‫܌‬Ңள‫ޕ‬Ǵ11c ‫ ܭ‬tubulin ϐ GDP 603 binding 68.

(76) site аణᗖ่ӝࣁЬǴϩձа҆ਡಃ 1 Տ࿼΢ϐణচηᆶಃ 4 Տ࿼΢ϐ਼চηᆶ tubulin ౢғϩη໔‫ޑ‬ణᗖբҔΚǴᆶ 11c ่ӝϐೈқ፦೽ՏǴϩձࢂữ୷ለ‫ׇ‬ӈಃ 179 ‫ ޑ‬Aspartic acid. (ASP)Ϸữ୷ለ‫ׇ‬ӈಃ 12 ‫ ޑ‬Cysteine(CYS). 3.4.3.4. 3'-Fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (11d)ϐϩηኳᔕ. O. 6. O 7. 5. 8. O 4. 3. N1 H. 2 1' 2' 3' F 6'. 4' 5'. 11d 3.4.3.4.1. 11d ‫ ܭ‬GTP 600 ϐ docking ႝတ຾Չ 11d ᆶ tubulin ϐ GTP 600 binding site. docking ่‫ࡕ״‬Ǵ๱‫ޣ‬җኳᔕ‫س‬಍ύᑔᒧр 10 ฽ၗ਑Ǵࢂа dock-score ଯե໩‫ׇ‬௨ӈԶԋǴ‫࣬ځ‬ᜢၗૻӵ Table 6-1Ǻ. 69.