| Co-Investigator(Kenkyū-buntansha) |
FUJIOKA Toshihiro Fukuoka University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (80165357)
YAMAGISHI Takashi Kitami Institute of Technology, Professor, 大学院・工学部, 教授 (80271758)
OKABE Hikaru Fukuoka University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (10078678)
NAGAO Tsuneatsu Fukuoka University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手 (90180455)
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| Research Abstract |
As a part of the structure-activity relationship study of the potent anti-HIV agent 3-Ο-(3', 3'-dimenthyl)-succinyl-betulinic acid(DSB), 3-Alkylamido-3-deoxy-betulinic acids were synthesized and evaluated for anti-HIV activity, 3-αDiglycorylamide-3-deoxy-betulinic acid demonstrated relatively potent anti-HIV activity(EC_<50> 0.24 μM, TI 728). However, replacing the ester group at C-3 in DSB and its analogues with an amido group yielded inactive or much less potent compounds against HIV replication, indicating that the ester group at C-3 in is essential for potent anti-HIV activity.
Four isomers of 3,28-di-Ο-(dimethylsuccinyl)-betulin were prepared and evaluated for anti-HIV activity against HIV-1 replication in H9 lymphocyte cells. 3-Ο-(3', 3'-Dimethylsuccinyl)-28-Ο-(2", 2"-dimethylsuccinyl)-betulin was the most potent anti-HIV compound with an EC_<50> value of 0.00087 μM and a TI value of 42,400.
3-Ο-Acyl-ursolic acids were prepared and evaluated their anti-HIV activities, based on our previous finding that 3-Ο-acyl-betulinic acid and -oleanolic acid, especially 3-Ο-(3', 3'-dimethyl)-succinyl-betulinic acid, and -oleanolic acid demonstrated potent anti-HIV activities(EC_<50> < 0.00035 and 0.00086 μM, respectively, therapeutic index(TI) > 20,000 and 22,326, respectively), as well as the fact that ursolic acid(6)showed similar level of anti-HIV activity(EC_<50> 4,4μM)to that of oleanolic acid(EC_<50> 3.7 μM), though it was slightly toxic(IC_<50> 14.3 μM, T.I.3.3). 3-Ο-Diglycoryl-ursolic acid demonstrated relatively potent anti-HIV activity with an EC_<50> 0.31 μM, and a TI of 155.5. In contrast, 3-Ο-(3', 3'-dimethylsuccinyl)-ursolic acid, corresponding to the extremely potent anti-HIV betulinic acid and oleanolic acid derivatives displayed only a weak anti-HIV activity(EC_<50> 2.1μM, T.I.23.6).
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