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The Anti-HIV Actions of 7- and 10-Substituted Camptothecins
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
School of Pharmacy, Lanzhou University, Lanzhou 730000, China
Graduate School of the Chinese Academy of Sciences, Beijing 100039, China
The First Affiliated Hospital of Kunming Medical College, Kunming, Yunnan 650032, China
Yunnan Institute of Dermatology & Venereology, Kunming, Yunnan 650032, China
* Authors to whom correspondence should be addressed.
Received: 22 November 2009; in revised form: 18 December 2009 / Accepted: 21 December 2009 / Published: 31 December 2009
Abstract: Camptothecin (CPT), a traditional anti-tumor drug, has been shown to possess anti-HIV-1 activity. To increase the antiviral potency, the anti-HIV activities of two CPT derivatives, 10-hydroxy-CPT and 7-hydroxymethyl-CPT, were evaluated in vitro. The therapy index (TI) of CPT, 10-hydroxy-CPT and 7-hydroxymethyl-CPT against HIV-1IIIB in C8166 were 24.2, 4.2 and 198.1, and against clinical isolated strain HIV-1KM018 in PBMC were 10.3, 3.5 and 66.0, respectively. While the TI of CPT, 10-hydroxy-CPT and 7-hydroxymethyl-CPT against HIV-2CBL-20 were 34.5, 10.7 and 317.0, respectively, and the TI of the three compounds against HIV-2ROD showed the similar values. However, when the antiviral mechanisms were considered, we found there was no inhibition of 7-hydroxymethyl-CPT on viral cell-to-cell transmission, and was no inhibition on reverse transcriptase, protease or integrase in cell-free systems. 7-Hydroxymethyl-CPT showed no selective killing of chronically infected cells after 3 days of incubation. In conclusion, 7-hydroxymethyl-CPT showed more potent anti-HIV activity, while 10-hydroxy-CPT had less efficient activity, compared with the parent CPT. Though the antiviral mechanisms remain to be further elucidated; the modification of -OH residues at C-7 of CPT could enhance the antiviral activity, while of -OH residues at C-10 of CPT had decreased the antiviral activity, which provides the preliminary modification strategy for anti-viral activities enhancement of this compound.
Keywords: camptothecin; anti-HIV agents; HIV
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Li, Y.-Y.; Chen, S.-W.; Yang, L.-M.; Wang, R.-R.; Pang, W.; Zheng, Y.-T. The Anti-HIV Actions of 7- and 10-Substituted Camptothecins. Molecules 2010, 15, 138-148.
Li Y-Y, Chen S-W, Yang L-M, Wang R-R, Pang W, Zheng Y-T. The Anti-HIV Actions of 7- and 10-Substituted Camptothecins. Molecules. 2010; 15(1):138-148.
Li, Yu-Ye; Chen, Shi-Wu; Yang, Liu-Meng; Wang, Rui-Rui; Pang, Wei; Zheng, Yong-Tang. 2010. "The Anti-HIV Actions of 7- and 10-Substituted Camptothecins." Molecules 15, no. 1: 138-148.