Synthesis and anti-HIV activity of cosalane analogues incorporating nitrogen in the linker chain.
Introduction of an amido group or an amino moiety into the alkenyl linker chain of cosalane (1) provided a new series of analogues 3-8. The new compounds were evaluated as inhibitors of the cytopathic effect of HIV-1 and HIV-2 in cell culture. The replacement of the 1' and 2' carbons in the linker chain of I by an amido group was generally tolerated. The length of the linker chain and the stereochemistry of the substituent at C-3 of the steroidal ring had significant effects on the antiviral activity and potency. Incorporation of an amino moiety into the linker completely abolished the anti-HIV activity. There are several steps in the HIV replication cycle that have been proposed as targets for the development of therapeutic agents (De Clercq, E. J. Med. Chem. 1995, 38, 2491; De Clercq, E. Pure Appl. Chem. 1998, 70, 567). However, currently approved anti-HIV drugs are only directed against the viral enzymes reverse transcriptase or protease (Carpenter. C. C. J.; Fischl, M. A.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S. G.; Richman, D. D.; Saag, M. S.; Schooley, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.; Volberding, P. A. JAMA 1998, 280, 78). Drugs capable of interfering with other steps of the virus life cycle will be highly valuable in the antiretroviral therapy of AIDS, as they will have different patterns of resistance mutations than the drugs currently used clinically. In addition, their utilization in combination with other therapeutic agents could provide more potent drug 'cocktails' capable of completely suppressing virus replication. Consequently, there is an urgent need for the discovery of clinically useful anti-HIV agents possessing novel mechanisms of action.
Casimiro-Garcia
A
A
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA.
De Clercq
E
E
Pannecouque
C
C
Witvrouw
M
M
Stup
T L
TL
Turpin
J A
JA
Buckheit
R W
RW
Cushman
M
M
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001312:Aurintricarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity; D015498:HIV-2 / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009584:Nitrogen / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment
D019380:Anti-HIV Agents; C083060:cosalane; D001312:Aurintricarboxylic Acid; D009584:Nitrogen