... Full Paper. Synthesis of New Camptothecin Analogues with the E-Lactone Ring Replaced by α,β-C... more ... Full Paper. Synthesis of New Camptothecin Analogues with the E-Lactone Ring Replaced by α,β-Cyclohexenone. Valeriy A. Bacherikov 1 ,; Tsong-Jen Tsai 1 ,; Jang-Yang Chang 2 ,; Ting-Chao Chou 3 ,; Rong-Zau Lee 1 ,; Tsann-Long Su 1. Article first published online: 9 AUG ...
A series of 5-(9-acridinylamino)anisidines were synthesized by condensing methoxy-substituted 1,3... more A series of 5-(9-acridinylamino)anisidines were synthesized by condensing methoxy-substituted 1,3-phenylenediamines (10 and 11) with 9-chloroacridine derivatives to form 5-(9-acridinylamino)-m-anisidines (AMAs, 14a-e) and 5-(9-acridinylamino)-o-anisidines (AOAs, 15a-e). 5-(9-Acridinylamino)-p-anisidines (APAs, 17a-e) were synthesized by reacting 2-methoxy-5-nitroaniline (12) with 9-anilinoacridines, followed by reduction. The cytotoxic inhibition of growth of various human tumor cells in culture, inhibitory effects against topoisomerase II, and DNA interaction of these agents were studied. The structure-activity relationship studies revealed the following degree of potency: AOAs > AMAs > APAs. They also revealed that the newly synthesized derivatives bearing CONH(2)NH(2)NMe(2) and Me substituents at C4 and C5 positions of the acridine chromophore (i.e., AMA 14e, AOA 15e, and APA 17e) exhibited significant cytotoxicity against human tumor cell growth in vitro. AOA (15e) was the most potent among these derivatives, which resulted in 60% suppression of tumor volume at a dose of 20 mg/kg (Q2D x 9), intravenous injection on day 26 in nude mice bearing human breast carcinoma MX-1 xenografts.
A series of non-classical antifolates, namely 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidin... more A series of non-classical antifolates, namely 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidines (25a-i) and 2,4-diamino-(N-phenylpyrrolidin-3-yl)-6(5H)-oxopyrimidines (26a,b,c,f,h,i) was synthesized and evaluated for their in vitro cytotoxicity. Reacting aniline derivatives with 1,4-dibromo-2-butanol gave 1-phenyl-3-pyrrolidinols (19a--i), which were oxidized to pyrrolidin-3-ones (20a-i). The Knoevenagel reaction of 20a-i with malononitrile or ethyl cyanoacetate gave 3-(dicyanomethylene)- (21a-i) and 3-[cyano(ethoxycarbonyl)methylene]-pyrrolidines (22a,b,c,f,h,i), respectively, which were subsequently reduced to the corresponding 3-(dicyano)methyl- or 3-[cyano(ethoxycarbonyl)methyl)]pyrrolidines (23a-i and 24a,b,c,f,h,i, respectively). Condensation of either 23a-i or 24a,b,c,f,h,i with guanidine afforded the target compounds. The cytotoxicity of these compounds was evaluated based on their ability to inhibit various human tumors (human colon adenocarcinoma COLO 205, lung carcinoma H23 and its adriamycin resistant cell line H23/0.3, T-cell leukemia MOLT-4, promyelocytic leukemia HL-60, and T-cell acute lymphocytic leukemia CCRF-CEM) cell growth in culture. These studies revealed that the 2,4,6-triaminopyrimidine derivatives were more cytotoxic than the 2,4-diamino-6(5H)-oxopyrimidine counter parts, in which the latter was inactive in all testing systems. The 2,4,6-triaminopyrimidine derivatives bearing halogen substituent on the phenyl ring (25f,h,i) were cytotoxic in all cultured leukemia cell growth. Among these compounds, 5-(4-fluoro and 4-chlorophenyl)-2,4,6-triaminopyrimidines (25e and 25h, respectively) were more potent than methotrexate (MTX) in inhibiting of H23/0.3 cell growth. These compounds inhibit the folate metabolic pathways as indicated by tritium release from [5-3H]deoxyuridine in MTX sensitive human fibrosarcoma HT-1080 cells. Dihydrofolate reductase is the major target for 25f,h,i, as shown by leucovorin (LV) rescue of MTX cytotoxicity.
... Full Paper. Synthesis of New Camptothecin Analogues with the E-Lactone Ring Replaced by α,β-C... more ... Full Paper. Synthesis of New Camptothecin Analogues with the E-Lactone Ring Replaced by α,β-Cyclohexenone. Valeriy A. Bacherikov 1 ,; Tsong-Jen Tsai 1 ,; Jang-Yang Chang 2 ,; Ting-Chao Chou 3 ,; Rong-Zau Lee 1 ,; Tsann-Long Su 1. Article first published online: 9 AUG ...
A series of 5-(9-acridinylamino)anisidines were synthesized by condensing methoxy-substituted 1,3... more A series of 5-(9-acridinylamino)anisidines were synthesized by condensing methoxy-substituted 1,3-phenylenediamines (10 and 11) with 9-chloroacridine derivatives to form 5-(9-acridinylamino)-m-anisidines (AMAs, 14a-e) and 5-(9-acridinylamino)-o-anisidines (AOAs, 15a-e). 5-(9-Acridinylamino)-p-anisidines (APAs, 17a-e) were synthesized by reacting 2-methoxy-5-nitroaniline (12) with 9-anilinoacridines, followed by reduction. The cytotoxic inhibition of growth of various human tumor cells in culture, inhibitory effects against topoisomerase II, and DNA interaction of these agents were studied. The structure-activity relationship studies revealed the following degree of potency: AOAs > AMAs > APAs. They also revealed that the newly synthesized derivatives bearing CONH(2)NH(2)NMe(2) and Me substituents at C4 and C5 positions of the acridine chromophore (i.e., AMA 14e, AOA 15e, and APA 17e) exhibited significant cytotoxicity against human tumor cell growth in vitro. AOA (15e) was the most potent among these derivatives, which resulted in 60% suppression of tumor volume at a dose of 20 mg/kg (Q2D x 9), intravenous injection on day 26 in nude mice bearing human breast carcinoma MX-1 xenografts.
A series of non-classical antifolates, namely 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidin... more A series of non-classical antifolates, namely 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidines (25a-i) and 2,4-diamino-(N-phenylpyrrolidin-3-yl)-6(5H)-oxopyrimidines (26a,b,c,f,h,i) was synthesized and evaluated for their in vitro cytotoxicity. Reacting aniline derivatives with 1,4-dibromo-2-butanol gave 1-phenyl-3-pyrrolidinols (19a--i), which were oxidized to pyrrolidin-3-ones (20a-i). The Knoevenagel reaction of 20a-i with malononitrile or ethyl cyanoacetate gave 3-(dicyanomethylene)- (21a-i) and 3-[cyano(ethoxycarbonyl)methylene]-pyrrolidines (22a,b,c,f,h,i), respectively, which were subsequently reduced to the corresponding 3-(dicyano)methyl- or 3-[cyano(ethoxycarbonyl)methyl)]pyrrolidines (23a-i and 24a,b,c,f,h,i, respectively). Condensation of either 23a-i or 24a,b,c,f,h,i with guanidine afforded the target compounds. The cytotoxicity of these compounds was evaluated based on their ability to inhibit various human tumors (human colon adenocarcinoma COLO 205, lung carcinoma H23 and its adriamycin resistant cell line H23/0.3, T-cell leukemia MOLT-4, promyelocytic leukemia HL-60, and T-cell acute lymphocytic leukemia CCRF-CEM) cell growth in culture. These studies revealed that the 2,4,6-triaminopyrimidine derivatives were more cytotoxic than the 2,4-diamino-6(5H)-oxopyrimidine counter parts, in which the latter was inactive in all testing systems. The 2,4,6-triaminopyrimidine derivatives bearing halogen substituent on the phenyl ring (25f,h,i) were cytotoxic in all cultured leukemia cell growth. Among these compounds, 5-(4-fluoro and 4-chlorophenyl)-2,4,6-triaminopyrimidines (25e and 25h, respectively) were more potent than methotrexate (MTX) in inhibiting of H23/0.3 cell growth. These compounds inhibit the folate metabolic pathways as indicated by tritium release from [5-3H]deoxyuridine in MTX sensitive human fibrosarcoma HT-1080 cells. Dihydrofolate reductase is the major target for 25f,h,i, as shown by leucovorin (LV) rescue of MTX cytotoxicity.
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