Anti-HIV

The National Cancer Institute (NCI) database is a collection of more than half a million structures, assembled by NCI s Developmental Therapeutics Program (DTP) or its predecessors in the course of NCTs anti-cancer screening efforts that started in the late 1950s (plus the more recent anti-HIV screening) [37-39]. Approximately half of this database is publicly available without any usage restrictions, and is therefore called the "Open NCI Database. For each of these structures (more than 250 000) the DTP record contains at least the chemical structure as a coimection table and an NCI accession number, the NSC number. 

CarbocycHc 2/3 -didehydro-2/3 -dideoxyguanosine [118353-05-2] (carbovk, CBV, 66), C H 2N502, synthesized in 1988 (177), is a promising candidate for the chemotherapy of AIDS. CBV inhibits HIV repHcation and HIV-induced cytopathic effects in a variety of human T-lymphoblastoid ceU lines at concentrations approximately two hundred- to four hundredfold below its cytotoxic concentrations (177). CBV is as effective as AZT and DDC in reducing the expression of vkal antigen in HIV-infected CEM ceUs (177). The antivkal potency and selectivity of carbovk is comparable to the anti-HIV-1 potency and selectivity of 2/3 -dideoxyadenosine (178). The exact mode of antivkal action of carbovk has not yet been elucidated, but may be the modulating effect of intraceUular nucleotides on 5 -nucleotidase activity (179). 

Recent advances in the discovery and development of plant-derived natural products and their analogs, in particular polycyclic 0-heterocycles, as anti-HIV agents 99PACI045. 

Heterocyclic sulfone derivatives with anti-HIV activity 97F321. 

Finke, P. E., Oates, B., Mills, S. G., MacCoss, M., Malkowitz, L., Springer, M. S., Gould, S. L., DeMartino, J. A., Carella, A. Carver, G., et al. (2001). Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4 synthesis and structure—Activity relationships for l-[7V-(Methyl)-7V-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(7V-(alkyl)-7V-(benzylox-ycarbonyl)amino)piperidin-l-yl)butanes. Bioorg. Med. Chem. Lett. 11 2475-2479. 

A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. AcadSci. USA 96 5698-5703. 

Naphtho[l, 2 4,5]thiazolo[3,2-h][l,2,4]triazines 1052 were prepared by cyclocondensation of aminoiminonaphthothiazole 1051 with an acetylenedicarboxylate. Methyl ester 1052 was tested in vitro for anti-HIV activity and was inactive (91MI6). 

Ivanova G, Arzumanov A A, Turner JJ et al (2006) Anti-HIV activity of steric block oligonucleotides. Ann NY Acad Sci 1082 103-115... 

Some 1,2,4-triazines having a 1,2,4-triazinone substituent, and some 1,2,4-triazolo[4,3-fc]-1,2,4-triazinones have been shown to have in vitro anti-HIV and anticancer activity < 95MI04 96CA(124)86961 >. 

Mitochondria-associated toxicities, such as pancreatitis, are frequently demonstrated in HlV/HCV-coinfected individuals, and may significantly influence treatment options (de Mendoza and Soriano 2005). Yet, no cell culture or animal models have been developed to predict nucleoside-induced pancreatitis. Nevertheless, an association of HCV replication and mitochondrial DNA depletion in primary human lymphocytes obtained from HIV/HCV-coinfected individuals under concomitant administration of HCV and HIV medications was demonstrated by de Mendoza and coworkers (de Mendoza et al. 2007). They claimed that the use of HCV medication together with certain antiretroviral agents seemed to enhance mitochondrial damage due to a synergistic deleterious interaction between the anti-HCV and anti-HIV drugs. In contrast, an improvement in mitochondrial content with effective... 

Storch CH, Theile D, Lindenmaier H, Haefeh WE, Weiss J (2007) Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein, Biochem Pharmacol 73 1573-1581... 

F. 3 Structural formulae of 2, 3 -dideoxynucleoside analogues (anti-HIV) agents... 

Wang J, Jin Y, Rapp KL, Schinazi RF, Chu CK (2007) D- and L-2, 3 -didehydro-2, 3 -dideoxy-3 -fluoro-carbocyclic nucleosides synthesis, anti-HIV activity and mechanism of resistance. J Med Chem 50 1828-1839... 

The second-generation NNRTIs usually require two or more mutations in the HIV-1 RT before a significant loss of antiviral potency occurs. Evidently, a markedly longer period of time is required before significant resistance against second-generation NNRTIs can arise, and therefore these compounds offer considerable promise as future anti-HIV-1 drugs. 

Ji C, Brandt M, Dioszegi M, Jekle A, Schwoerer S, ChaUand S, Zhang J, Chen Y, Zautke L, Achhammer G, Baehner M, Kroetz S, HeUek-Snyder G, Schumacher R, Cammack N, Sankuratri S (2007) Novel CCR5 monoclonal antibodies with potent and broad-spectrum anti-HIV activities. Antiviral Res 74 125-137... 

IhRNAs have also been used to induce an anti-HIV-1 RNAi response (Barichievy et al. 2007 Konstantinova et al. 2006, 2007 Liu et al. 2007). These IhRNAs can be processed into multiple effective siRNAs, thus preventing the chance of viral escape. Although IhRNA have been shown to effectively inhibit HIV-1 replication, there is currently no data on their ability to prevent viral escape. The use of multiple siRNAs or IhRNAs should take into account the increased danger of side effects due to interference with cellular miRNA processing and function. 

Li MJ, Kim J, Li S, Zaia J, Yee JK, Anderson J, Akkina R, Rossi JJ (2005b) Long-term inhibition of HlV-1 infection in primary hematopoietic cells by lentiviral vector delivery of a triple combination of anti-HIV shRNA, anti-CCR5 ribozyme, and a nucleolar-localizing TAR decoy. Mol Ther 12 900-909... 

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