Potent, Orally Active Heterocycle-Based Combretastatin A-4 Analogues: Synthesis, Structure−Activity Relationship, Pharmacokinetics, and In Vivo Antitumor Activity Evaluation
Le Wang
1
,
Keith W. Woods
1
,
Q. Li
1
,
Kenneth J Barr
1
,
Richard W. McCroskey
1
,
Steven M Hannick
1
,
Laura Gherke
1
,
R.Bruce Credo
1
,
Yu-Hua Hui
1
,
Kennan Marsh
1
,
Robert Warner
1
,
Jang Y. Lee
1
,
Nicolette Zielinski Mozng
1
,
David Frost
1
,
Saul H. Rosenberg
1
,
Hing L. Sham
1
1
Global Pharmaceutical R & D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101
|
Publication type: Journal Article
Publication date: 2002-03-13
scimago Q1
wos Q1
SJR: 1.801
CiteScore: 11.5
Impact factor: 6.8
ISSN: 00222623, 15204804
PubMed ID:
11931625
Drug Discovery
Molecular Medicine
Abstract
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.
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Metrics
375
Total citations:
375
Citations from 2024:
19
(5.07%)
Cite this
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MLA
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GOST
Copy
Wang L. et al. Potent, Orally Active Heterocycle-Based Combretastatin A-4 Analogues: Synthesis, Structure−Activity Relationship, Pharmacokinetics, and In Vivo Antitumor Activity Evaluation // Journal of Medicinal Chemistry. 2002. Vol. 45. No. 8. pp. 1697-1711.
GOST all authors (up to 50)
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Wang L., Woods K. W., Li Q., Barr K. J., McCroskey R. W., Hannick S. M., Gherke L., Credo R., Hui Y., Marsh K., Warner R., Lee J. Y., Zielinski Mozng N., Frost D., Rosenberg S. H., Sham H. L. Potent, Orally Active Heterocycle-Based Combretastatin A-4 Analogues: Synthesis, Structure−Activity Relationship, Pharmacokinetics, and In Vivo Antitumor Activity Evaluation // Journal of Medicinal Chemistry. 2002. Vol. 45. No. 8. pp. 1697-1711.
Cite this
RIS
Copy
TY - JOUR
DO - 10.1021/jm010523x
UR - https://doi.org/10.1021/jm010523x
TI - Potent, Orally Active Heterocycle-Based Combretastatin A-4 Analogues: Synthesis, Structure−Activity Relationship, Pharmacokinetics, and In Vivo Antitumor Activity Evaluation
T2 - Journal of Medicinal Chemistry
AU - Wang, Le
AU - Woods, Keith W.
AU - Li, Q.
AU - Barr, Kenneth J
AU - McCroskey, Richard W.
AU - Hannick, Steven M
AU - Gherke, Laura
AU - Credo, R.Bruce
AU - Hui, Yu-Hua
AU - Marsh, Kennan
AU - Warner, Robert
AU - Lee, Jang Y.
AU - Zielinski Mozng, Nicolette
AU - Frost, David
AU - Rosenberg, Saul H.
AU - Sham, Hing L.
PY - 2002
DA - 2002/03/13
PB - American Chemical Society (ACS)
SP - 1697-1711
IS - 8
VL - 45
PMID - 11931625
SN - 0022-2623
SN - 1520-4804
ER -
Cite this
BibTex (up to 50 authors)
Copy
@article{2002_Wang,
author = {Le Wang and Keith W. Woods and Q. Li and Kenneth J Barr and Richard W. McCroskey and Steven M Hannick and Laura Gherke and R.Bruce Credo and Yu-Hua Hui and Kennan Marsh and Robert Warner and Jang Y. Lee and Nicolette Zielinski Mozng and David Frost and Saul H. Rosenberg and Hing L. Sham},
title = {Potent, Orally Active Heterocycle-Based Combretastatin A-4 Analogues: Synthesis, Structure−Activity Relationship, Pharmacokinetics, and In Vivo Antitumor Activity Evaluation},
journal = {Journal of Medicinal Chemistry},
year = {2002},
volume = {45},
publisher = {American Chemical Society (ACS)},
month = {mar},
url = {https://doi.org/10.1021/jm010523x},
number = {8},
pages = {1697--1711},
doi = {10.1021/jm010523x}
}
Cite this
MLA
Copy
Wang, Le, et al. “Potent, Orally Active Heterocycle-Based Combretastatin A-4 Analogues: Synthesis, Structure−Activity Relationship, Pharmacokinetics, and In Vivo Antitumor Activity Evaluation.” Journal of Medicinal Chemistry, vol. 45, no. 8, Mar. 2002, pp. 1697-1711. https://doi.org/10.1021/jm010523x.