Potent antitumor bifunctional DNA alkylating agents, synthesis and biological activities of 3a-aza-cyclopenta[a]indenes.
A series of bifunctional DNA interstrand cross-linking agents, bis(hydroxymethyl)- and bis(carbamates)-8H-3a-azacyclopenta[a]indene-1-yl derivatives were synthesized for antitumor evaluation. The preliminary antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro and antitumor therapeutic efficacy against human tumor xenografts in vivo. Furthermore, these derivatives have little or no cross-resistance to either Taxol or Vinblastine. Remarkably, complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft by 13a,b and 14g,h and significant suppression against prostate adenocarcinoma PC3 xenograft by 13b were achieved at the maximum tolerable dose with relatively low toxicity. In addition, these agents induce DNA interstrand cross-linking and substantial G2/M phase arrest in human non-small lung carcinoma H1299 cells. The current studies suggested that these agents are promising candidates for preclinical studies.
Kakadiya
Rajesh
R
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
Dong
Huajin
H
Lee
Pei-Chih
PC
Kapuriya
Naval
N
Zhang
Xiuguo
X
Chou
Ting-Chao
TC
Lee
Te-Chang
TC
Kapuriya
Kalpana
K
Shah
Anamik
A
Su
Tsann-Long
TL
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D002277:Carcinoma / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy; D012074:Remission Induction; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D001372:Aza Compounds; D003432:Cross-Linking Reagents; D007192:Indenes; D004247:DNA