TY - JOUR
T1 - Antineoplastic Agents. 605. Isoquinstatins
AU - Pettit, George
AU - Melody, Noeleen
AU - Chapuis, Jean
N1 - Funding Information:
With appreciation, we acknowledge and thank for financial support the Arizona Biomedical Research Commission, the J.W. Kiecknefer Foundation, and the Margaret T. Morris Foundation.
Publisher Copyright:
© 2017 American Chemical Society and American Society of Pharmacognosy.
PY - 2018/3/23
Y1 - 2018/3/23
N2 - In order to further explore quinoline-type structural modification of the powerful anticancer drug dolastatin 10, an Indian Ocean sea hare constituent and parent molecule of the very successful antibody drug conjugate (ADC) Adcetris, our recent quinstatin study has been extended by replacing the quinoline ring with an isoquinoline. The resulting isoquinstatins (4-6) were modified to N-terminal desmethylisoquinstatins (7-9) and, in turn, bonded to appropriate linker units to give linker-desmethylisoquinstatin conjugates 11-13 in preparation for eventual monoclonal antibody attachment. Comparison of the new isoquinstatins with their quinstatin counterparts against six human cancer cell lines indicated the isoquinstatins to have GI 50 values that were comparable to or somewhat higher than those of the isomeric quinstatins. However, desmethylisoquinstatin 5 (7) was significantly more potent than its desmethylquinstatin 5 analogue. When evaluated against quinstatin 8, its isoquinstatin 8 (6) counterpart was somewhat less potent. In general, the isoquinstatins evaluated proved to be quite strong cancer cell growth inhibitors.
AB - In order to further explore quinoline-type structural modification of the powerful anticancer drug dolastatin 10, an Indian Ocean sea hare constituent and parent molecule of the very successful antibody drug conjugate (ADC) Adcetris, our recent quinstatin study has been extended by replacing the quinoline ring with an isoquinoline. The resulting isoquinstatins (4-6) were modified to N-terminal desmethylisoquinstatins (7-9) and, in turn, bonded to appropriate linker units to give linker-desmethylisoquinstatin conjugates 11-13 in preparation for eventual monoclonal antibody attachment. Comparison of the new isoquinstatins with their quinstatin counterparts against six human cancer cell lines indicated the isoquinstatins to have GI 50 values that were comparable to or somewhat higher than those of the isomeric quinstatins. However, desmethylisoquinstatin 5 (7) was significantly more potent than its desmethylquinstatin 5 analogue. When evaluated against quinstatin 8, its isoquinstatin 8 (6) counterpart was somewhat less potent. In general, the isoquinstatins evaluated proved to be quite strong cancer cell growth inhibitors.
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U2 - 10.1021/acs.jnatprod.7b00352
DO - 10.1021/acs.jnatprod.7b00352
M3 - Article
C2 - 28926240
AN - SCOPUS:85044532897
SN - 0163-3864
VL - 81
SP - 451
EP - 457
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 3
ER -