Antihuman Immunodeficiency Virus Type 1 (HIV-1) Activity of Rare Earth Metal Complexes of 4-Hydroxycoumarins in Cell Culture

Manolov, Ilia; Raleva, Sevda; Genova, Petya; Savov, Alexey; Froloshka, Liliana; Dundarova, Daniela; Argirova, Radka

doi:https://doi.org/10.1155/BCA/2006/71938

Bioinorganic Chemistry and Applications

On this page

Abstract References Copyright Related Articles

Open Access

Volume 2006 | Article ID 071938 | https://doi.org/10.1155/BCA/2006/71938

Antihuman Immunodeficiency Virus Type 1 (HIV-1) Activity of Rare Earth Metal Complexes of 4-Hydroxycoumarins in Cell Culture

Ilia Manolov,¹Sevda Raleva,²Petya Genova,²Alexey Savov,³Liliana Froloshka,²Daniela Dundarova,²and Radka Argirova²

Received23 Dec 2004

Revised09 Mar 2005

Accepted17 Jun 2005

Published28 Feb 2006

Abstract

The cerium Ce(III), lanthanum La(III), and neodymium Nd(III) complexes with 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one (warfarin) (W) and 3,3′-benzylidenebis[4-hydroxycoumarin] (1) were synthesized and studied for the first time for cytotoxicity (on MT-2 cells) and as anti-HIV agents under acute and chronic infection. The complexes were characterized by different physicochemical methods: mass spectrometry, ¹H NMR, ¹³C NMR, and IR spectroscopy. The spectra of the complexes were interpreted on the basis of comparison with the spectrum of the free ligands. Anti-HIV effect of the complexes/ligands was measured in MT-2 cells by microtiter infection assay. Detection of endogenous reverse transcriptase (RT) activity and RT processivity by PCR indicative for proviral DNA synthesis demonstrated that anti-HIV activity has not been linked to early stages of viral replication. No effect on late steps of viral replication has been found using cells chronically producing HIV-1LAI virus. La(W) demonstrated anti-HIV activity (IC50=21.4μM) close to maximal nontoxic concentration. Nd(W), Ce(1), and Nd(1) demonstrated limited anti-HIV potency, so none of the complexes seems appropriate to be used in clinic. Further targeting of HIV-1 inhibition by La(W) is under progress.

References

P Zhou, Y Takaishi, H Duan et al., “Coumarins and bicoumarin from Ferula sumbul: anti-HIV activity and inhibition of cytokine release,” Phytochemistry, vol. 53, no. 6, pp. 689–697, 2000.
View at: Google Scholar
I Kostova, S Raleva, P Genova, and R Argirova, “Recent advances in the discovery and development of plant-derived natural coumarins and their analogues as anti human immunodeficiency virus–type 1 (HIV-1) agents,” Biotechnology and Biotechnological Equipment, vol. 19, no. 1, pp. 16–22, 2005.
View at: Google Scholar
X Shao, D HL Ekstrand, R Bhikhabhai, C FR Kallander, and J S Gronowitz, “A non-radioactive microtiter plate reverse transcriptase (RT) assay, based on immobilized template, for screening of RT activity inhibitors and evaluation of their mofe of action,” Antiviral Chemistry & Chemotherapy, vol. 8, no. 2, pp. 149–159, 1997.
View at: Google Scholar
S Thaisrivongs, K D Watenpaugh, W J Howe et al., “Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors,” Journal of Medicinal Chemistry, vol. 38, no. 18, pp. 3624–3637, 1995.
View at: Google Scholar
C Spino, M Dodier, and S Sotheeswaran, “Anti-HIV coumarins from Calophyllum seed oil,” Bioorganic & Medicinal Chemistry Letters, vol. 8, no. 24, pp. 3475–3478, 1998.
View at: Google Scholar
Z Q Xu, E R Kern, L Westbrook et al., “Plant-derived and semi-synthetic calanolide compounds with in vitro activity against both human immunodeficiency virus type 1 and human cytomegalovirus,” Antiviral Chemistry & Chemotherapy, vol. 11, no. 1, pp. 23–29, 2000.
View at: Google Scholar
Y Kashman, K R Gustafson, R W Fuller et al., “The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum,” Journal of Medicinal Chemistry, vol. 35, no. 15, pp. 2735–2743, 1992.
View at: Google Scholar
A Mazumder, S Wang, N Neamati et al., “Antiretroviral agents as inhibitors of both human immunodeficiency virus type 1 integrase and protease,” Journal of Medicinal Chemistry, vol. 39, no. 13, pp. 2472–2481, 1996.
View at: Google Scholar
F Rosskopf, J Kraus, and G Franz, “Immunological and antitumor effects of coumarin and some derivatives,” Die Pharmazie, vol. 47, no. 2, pp. 139–142, 1992.
View at: Google Scholar
P McCulloch and W D George, “Warfarin inhibits metastasis of Mtln3 rat mammary carcinoma without affecting primary tumour growth,” British Journal of Cancer, vol. 59, no. 2, pp. 179–183, 1989.
View at: Google Scholar
I Kostova, I Manolov, S Konstantinov, and M Karaivanova, “Synthesis, physicochemical characterisation and cytotoxic screening of new complexes of cerium, lanthanum and neodymium with Warfarin and Coumachlor sodium salts,” European Journal of Medicinal Chemistry, vol. 34, no. 1, pp. 63–68, 1999.
View at: Google Scholar
I P Kostova, I I Manolov, I N Nicolova, and N D Danchev, “New metal complexes of 4-methyl-7-hydroxycoumarin sodium salt and their pharmacological activity,” Il Farmaco, vol. 56, no. 9, pp. 707–713, 2001.
View at: Google Scholar
I Kostova, I Manolov, I Nicolova, S Konstantinov, and M Karaivanova, “New lanthanide complexes of 4-methyl-7-hydroxycoumarin and their pharmacological activity,” European Journal of Medicinal Chemistry, vol. 36, no. 4, pp. 339–347, 2001.
View at: Google Scholar
I Manolov, I Kostova, S Konstantinov, and M Karaivanova, “Synthesis, physicochemical characterization and cytotoxic screening of new complexes of cerium, lanthanum and neodymium with Niffcoumar sodium salt,” European Journal of Medicinal Chemistry, vol. 34, no. 10, pp. 853–858, 1999.
View at: Google Scholar
I Manolov, I Kostova, T Netzeva, S Konstantinov, and M Karaivanova, “Cytotoxic activity of cerium complexes with coumarin derivatives. Molecular modeling of the ligands,” Archiv der Pharmazie: Pharmaceutical and Medicinal Chemistry, vol. 333, no. 4, pp. 93–98, 2000.
View at: Google Scholar
D C Montefiori, W E Jr Robinson, S S Schuffman, and W M Mitchell, “Evaluation of antiviral drugs and neutralizing antibodies to human immunodeficiency virus by a rapid and sensitive microtiter infection assay,” Journal of Clinical Microbiology, vol. 26, no. 2, pp. 231–235, 1988.
View at: Google Scholar
J A Zack, S J Arrigo, S R Weitsman, A S Go, A Haislip, and I S Chen, “HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure,” Cell, vol. 61, no. 2, pp. 213–222, 1990.
View at: Google Scholar
D J Hazuda, P Felock, M Witmer et al., “Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells,” Science, vol. 287, no. 5453, pp. 646–650, 2000.
View at: Google Scholar

Copyright

Copyright © 2006 Ilia Manolov et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation Order printed copies

Views

407

Downloads

1022

Citations