- An Enantioselective Total Synthesis of (+)-Duocarmycin SA
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An efficient, concise enantioselective total synthesis of the potent antitumor antibiotic (+)-duocarmycin SA is described. The invented route is based on a disconnection strategy that was devised to facilitate rapid and efficient synthesis of key core compounds to enable preclinical structure-activity relationship investigations. The key tricycle core was constructed with a highly enantioselective indole hydrogenation to set the stereocenter and a subsequent hitherto unexplored vicarious, nucleophilic-substitution/cyclization sequence to effectively forge a final indole ring. Additionally, the development of a stable sulfonamide protecting group capable of mild chemoselective cleavage greatly enhanced sequence yield and throughput. An understanding of key reaction parameters ensured a robust, reproducible sequence easily executable on decagram scales to this highly promising class of compounds.
- Schmidt, Michael A.,Simmons, Eric M.,Wei, Carolyn S.,Park, Hyunsoo,Eastgate, Martin D.
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- Structural influence of indole C5-N-substitutents on the cytotoxicity of seco-duocarmycin analogs
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A series of racemic indole C5-substituted seco-cyclopropylindoline compounds (2,3 and 5-7) were prepared by coupling 1-(tert-butyloxycarbonyl)-3- (chlorocarbonyl)indoline (seg-A) with 5,6,7-trimethoxy-, 5,6-dimethoxy-, 5-amino-, 5-methylsulfonylamino- and 5-(N,N-dimethylaminosulfonylamino) indole-2-carboxylic acid as seg-B in the presence of 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide. The synthetic compounds (2,3 and 5-7) were tested for cytotoxic activity against human cancer cell lines (COLO 205, SK-MEL-2, A549, and JEG-3) using the MTT assay.
- Choi, Taeyoung,Ma, Eunsook
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p. 357 - 367
(2012/05/04)
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- Synthesis and anti-tumor activity of 2-amino-3-cyano-6-(1H-indol-3-yl)-4- phenylpyridine derivatives in vitro
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A series of novel 2-amino-3-cyano-6-(1H-indol-3-yl)-4-phenylpyridine derivatives were synthesized and their cytotoxic activity against A549, H460, HT-29 and SMMC-7721 cell lines was evaluated in vitro. Among them, ten compounds (10, 11, 14, 16, 17, 26, 27, 29, 30 and 31) displayed excellent anti-tumor activity against different cell lines. The most promising compound 27 showed strong anti-tumor activity against A549, H460, HT-29 and SMMC-7721 cell lines with IC50 values of 22, 0.23, 0.65 and 0.77 nM, which were 2.6-, 83-, 1.1 × 103- and 2.0 × 103- fold more active than MX-58151 (IC50 values of 0.058, 0.019, 0.70 and 1.53 μM), respectively.
- Zhang, Fan,Zhao, Yanfang,Sun, Li,Ding, Lu,Gu, Yucheng,Gong, Ping
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p. 3149 - 3157
(2011/06/26)
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- Cyclic diamine compound with condensed-ring groups
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A cyclic diamine compound of formula (1): wherein R1 and R2 are individually a hydrogen atom or a methoxy group, provided R1 is a methoxy group when R2 is a hydrogen atom, or a hydrogen atom when R2 is a methoxy group; A is an oxygen atom, a sulfur atom, CH═CH, CH═N or NR3, in which R3 is a hydrogen atom, or a lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, aryl or aryl lower alkyl group; B is a nitrogen atom, CH or CR4, in which R4 is a hydrogen atom, or a lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, aryl or aryl lower alkyl group; m is 1 or 2; and n is a number of 1 to 5, an acid-addition salt thereof, or a hydrate thereof. The compound has inhibitory effects on cell adhesion and is useful for treatment of allergy, asthma, rheumatism, arteriosclerosis, and inflammation.
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- Total synthesis of the duocarmycins
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The total synthesis of (+)-duocarmycin A and SA through a common indoline intermediate is described. The key reactions include selective lithiation of a 2,6-dibromoiodobenzene derivative and diastereoselective addition to a chiral nitroalkene, copper-mediated aryl amination, and addition of aryllithium to azlactones. Copyright
- Yamada, Ken,Kurokawa, Toshiki,Tokuyama, Hidetoshi,Fukuyama, Tohru
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p. 6630 - 6631
(2007/10/03)
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- Synthetic Studies on Duocarmycin. 1. Total Synthesis of dl-Duocarmycin A and Its 2-Epimer
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The title synthesis was first achieved by employing novel methoxycarbonylation of the C4-position of the 5-aminoindoline by way of the isatin and subsequent Dieckmann cyclization to the methyl 2-methylindoxyl-2-carboxylate as key steps.In vitro cytotoxicity assay against P388 murine leukemia obviously disclosed that cytotoxicities of the synthesized compounds are comparable and almost half of that of natural (+)-duocarmycin A. - Key Words: dl-duocarmycin A, dl-2-epi-duocarmycin A, total synthesis, antitumor antibiotic, cytotoxicity
- Fukuda, Yasumichi,Itoh, Yoshio,Nakatani, Kazuhiko,Terashima, Shiro
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p. 2793 - 2808
(2007/10/02)
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- First total synthesis of dl-duocarmycin A
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The title synthesis could be achieved by featuring introduction of a methoxycarbonyl group into the C-4 position of a 5-aminoindoline nucleus by way of an isatin derivative and subsequent ring closure to a methyl 2-methylindoxyl-2-carboxylate system by the Dieckmann cyclization.
- Fukuda, Yasumichi,Nakatani, Kazuhiko,Ito, Yoshio,Terashima, Shiro
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p. 6699 - 6702
(2007/10/02)
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