Synthesis and biological evaluation of N-heterocyclic indolyl glyoxylamides as orally active anticancer agents.
A series of N-heterocyclic indolyl glyoxylamides were synthesized and evaluated for in vitro and in vivo anticancer activities. They exhibited a broad spectrum of anticancer activity not only in murine leukemic cancer cells but also in human gastric, breast, and uterus cancer cells as well as their multidrug resistant sublines with a wide range of IC(50) values. They also induced apoptosis and caused DNA fragmentation in human gastric cancer cells. Among the compounds studied, 7 showed the most potent activity of growth inhibition (IC(50) = 17-1711 nM) in several human cancer cells. Given orally, compounds 7 and 13 dose-dependently prolonged the survival of animals inoculated with P388 leukemic cancer cells. N-Heterocyclic indolyl glyoxylamides may be useful as orally active chemotherapeutic agents against cancer and refractory cancerous diseases of multidrug resistance phenotype.
Li
Wen-Tai
WT
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 9F, 161, Sec. 6, Min-Chiuan East Road, Nei-Hu, Taipei 114, Taiwan, ROC.
Hwang
Der-Ren
DR
Chen
Ching-Ping
CP
Shen
Chien-Wei
CW
Huang
Chen-Long
CL
Chen
Tung-Wei
TW
Lin
Chi-Hung
CH
Chang
Yee-Ling
YL
Chang
Ying-Ying
YY
Lo
Yue-Kan
YK
Tseng
Huan-Yi
HY
Lin
Chu-Chung
CC
Song
Jeng-Shin
JS
Chen
Hua-Chien
HC
Chen
Shu-Jen
SJ
Wu
Se-Hui
SH
Chen
Chiung-Tong
CT
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006038:Glyoxylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007941:Leukemia P388 / Q000401:mortality; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006038:Glyoxylates; D007211:Indoles; C474151:N1-(3-methyl-5-isothiazolyl)-2-(1-(4-cyanobenzyl)-1H-3-indolyl)-2-oxoacetamide; C474150:N1-(3-methyl-5-isothiazolyl)-2-1-((3-methyl-5-isoxazolyl)methyl)-1H-3-indolyl-2-oxoacetamide; D013844:Thiazoles