Potent, orally active heterocycle-based combretastatin A-4 analogues: synthesis, structure-activity relationship, pharmacokinetics, and in vivo antitumor activity evaluation.
The synthesis and structure-activity relationship study of a series of compounds with heterocycles in place of the cis double bond in combretastatin A-4 (CA-4) are described. Substituted tosylmethyl isocyanides were found to be the key intermediates in construction of the heterocycles. Cytotoxicities of the heterocycle-based CA-4 analogues were evaluated against NCI-H460 and HCT-15 cancer cell lines. 3-Amino-4-methoxyphenyl and N-methyl-indol-5-yl were the best replacements for the 3-hydroxy-4-methoxyphenyl in CA-4. 4,5-Disubstituted imidazole was found to be the best for the replacement of the cis double bond in CA-4. Medicinal chemistry efforts led to the discovery of compounds 24h and 25f that were found to be 32 and 82% bioavailable, respectively, in rat. Evaluation of 24h and 25f against murine M5076 reticulum sarcoma in mice revealed that both compounds were orally efficacious with an increase in life span of 38.5 and 40.5%, respectively.
Wang
Le
L
Global Pharmaceutical R & D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101, USA. le.wang@abbott.com
Woods
Keith W
KW
Li
Qun
Q
Barr
Kenneth J
KJ
McCroskey
Richard W
RW
Hannick
Steven M
SM
Gherke
Laura
L
Credo
R Bruce
RB
Hui
Yu-Hua
YH
Marsh
Kennan
K
Warner
Robert
R
Lee
Jang Y
JY
Zielinski-Mozng
Nicolette
N
Frost
David
D
Rosenberg
Saul H
SH
Sham
Hing L
HL
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001704:Biopolymers; D002455:Cell Division / Q000187:drug effects; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D000882:Haplorhini; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000737:chemistry; D014407:Tumor Cells, Cultured
C453487:1-methyl-4-(3,4,5-trimethoxyphenyl)-5-(3,4-bis(2-(methylamino)ethyl)phenyl)imidazole; C453486:1-methyl-4-(3,4,5-trimethoxyphenyl)-5-(3-amino-4-methoxyphenyl)imidazole; D000970:Antineoplastic Agents; D001704:Biopolymers; D007093:Imidazoles; D013267:Stilbenes; D014404:Tubulin; C058728:fosbretabulin