HIV activity

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

Schols D, Proost P, Struyf S et al (1998) CD26-processed RANTES(3-68), but not intact RANTES, has potent anti-HIV-1 activity. Antiviral Res 39 175-187 Schonbeck U, Mach F, Libby P (1998) Generation of biologically active IL-1 beta by matrix metaUoproteinases a novel caspase-1-independent pathway of IL-1 beta processing. J Immunol 161 3340-3346... 

Oravecz T, Pall M, Wang J, Roderiquez G, Ditto M, Norcross MA. Regulation of anti-HIV-1 activity of RANTES by heparan sulfate proteoglycans. J Immunol 1997 159(9) 4587 1592. 

The HEPT and TIBO derivatives were discovered as the result of a systematic evaluation for anti-HIV activity in cell culture. They were later found to achieve their anti-HIV-1 activity through an interaction with the HIV-1 RT. In contrast, nevirapine, pyridinone, and BHAP emerged from a screening program for HIV-1 RT inhibitors. The anti-HIV-1 activity of these compounds was subsequently confirmed in cell culture. Like the HEPT and TIBO derivatives, the 2, 5 -bis-0-(tert-butyldimethylsilyl)-3 -spiro-5" -(4" -amino-1", 2" -oxathiole-2", 2" -dioxide)-pyrimidine (TS AO) derivatives (Fig. 9) [65,66] and a-anilinophenylacetamides (a-APA) (Fig. 10) [67] were discovered through the evaluation of their anti-HIV activity in cell culture. Subsequently, they were found to act as specific inhibitors of HIV-1 RT. 

Mertens A, Zilch H, Konig B, Schafer W, Poll T, Kampe W, Seidel H, Leser U, Leinert H. Selective non-nucleoside HIV-1 reverse transcriptase inhibitors. New 2,3-dihydrothiazolo[2,3-a]isoindol-5(97>77)-ones and related compounds with anti-HIV-1 activity. J Med Chem 1993 36 2526-2535. 

Reviews of saturated oxygen heterocycles <00JCS(P1)1291>, routes to 2,2-dimethyl-2H-[l]benzopyrans <00H(53)1193> and pyranonaphthoquinone antibiotics <00T1937>, HIV-1 active Calophyllum coumarins <00H(53)453> and of the application of (3-halovinylaldehydes in heterocyclic synthesis <00H(53)941> have appeared. 

New synthetic pathways have been elaborated for imidazo[l,2-3][l,2,4]benzodithiazines (i.e., analogues of 182) <2006BML2985, 2006BML5298>. The new derivatives exhibited remarkable antitumor and anti-HIV-1 activity. 

In the future, studies testing co-administration of HDAC inhibitor and an activator such as IL7 or prostratin-like agent, together with intensified HAART, could offer a new hope for HIV-1-infected patients. This type of clinical protocol could provoke a drastic HIV-1 activation leading to a strong decline of HIV-1 reservoir level, sufficiently to allow HIV-1 remission. 

In 1990, Lange et al. isolated O-methylmukonal (38) from the roots of Murray a siamensis (57). Two years later, Bhattacharyya et al. reported the isolation of the same alkaloid from the roots of a different natural source, G. pentaphylla, and named it glycosinine (38) (24). More recently, Kongkathip et al. reported the isolation of O-methylmukonal (38) from the rhizomes and the roots of another natural source, C. excavata (58). Moreover, they reported for the first time that 38 showed anti-HIV-1 activity. 

In 1996, Wu et al. isolated clausine H (50) and clausine K (51) from the stem bark of C. excavata (46). These alkaloids showed an inhibition of rabbit platelet aggregation and caused vasocontraction. Later, Ito et al. isolated clausine H and clausine K from the same natural source and named them clauszoline C (50) (74) and clauszoline-J (51) (47). More recently, Kongkathip et al. isolated clauszoline-J (51) from the rhizomes and roots of the same natural source, C. excavata, and described its anti-HIV-1 activity (58). 

In 2000, Boyd et al. reported for the first time an anti-HIV active carbazole alkaloid, siamenol (89) (see Scheme 2.17). This prenylated carbazole alkaloid inhibited HIV-1 induced cytopathic inhibitor activity in an XTT-tetrazolium assay with EC50 2.6 pg/mL (85,449). Recently, Kongkathip et al. reported anti-HIV-1 activity for O-methylmukonal (glycosinine) (38) (see Scheme 2.9), 7-methoxy-O-methylmu-konal (2,7-dimethoxy-3-formylcarbazole) (48) (see Scheme 2.10), and clausine K (clausazoline-J) (51). These studies showed strong anti-HIV-1 activity for... 

The discovery of spirocyclic nucleosides with anti-HIV-1 activity has prompted Chattopadhyaya and co-workers (54,55) to prepare spiroisoxazolidine nucleosides (Scheme 1.6). Thus, after proving the reactivity of related systems in an... 

Proteomics have been used to develop biomarkers. This is achieved by comparative analysis of protein expression in healthy and diseased tissues to identify expressed proteins to be used as new markers, by analysis of secreted proteins in cell lines and primary cultures, and by direct serum protein profiling. MALDI seems to be a good technique for direct protein analysis in biological fluids (e.g., the identification of the small proteins-defensin 1, 2 and 3 as related to the anti-HIV-1 activity of CD8 antiviral factor). 

Avarol and avarone derivatives (from the Red Sea sponge Dysidea cinerea), the alkaloids psy-chotrine and O-methylpsychotrine (from ipecac, the dried rhizome and root of Cephaelis ipecacuanha), and phloroglucinol derivatives such as mallotojaponin, from the pericarps of Mallotus japonicus, have all been reported to inhibit the reverse transcriptase activity of HIV-1, noncom-petitively with respect to the natural substrate (dNTP). In neither case was the anti-HIV-1 activity determined in cell culture, so it is not clear whether any of these compounds is really an effective... 

Zalcitabine (ddC) is a cytosine analog (Figure 49-4) that has synergistic anti-HIV-1 activity with a variety of antiretroviral agents against both zidovudine-sensitive and zidovudine-resistant strains of HIV-1. 

M. Kuipers, M. Witvrouw, J. Este, E. De Clercq, D. Meijer, and P. Swart, Anti-HIV-1 activity of combinations and covalent conjugates of negatively charged albumins and AZT, Clin. Pharmacokinet. 73 131-140 (1998). 

Later a trivalent version of CD4M9 miniprotein (Fig. 1) was synthesized and was reported to have -140-fold enhanced anti-HIV-1 activity compared with the monovalent miniprotein (11). 

Lusso P, Vangelista L, Cimbro R et al (2011) Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity. FASEB J 25 1230-1243... 

Chen et al. recently reported the stable ruthenium-oxo-oxalato cluster Na7[Ru4(p3-0)4(C204)g] (2) (Fig. lc) as a particularly potent inhibitor of HIV-1 reverse transcriptase (RT) with an IC50 value of 1.9 nM [17], Apparently, the polyanionic cluster mimics poly anionic nucleic acid in its binding to HIV-1 RT through electrostatic interactions. The cluster shows promising anti-HIV-1 activity without being cytotoxic. In contrast to many polyoxometallates, this cluster has been demonstrated to be stable under physiological conditions. 

Ethanol extract of the fruit peel of G. mangostana showed potent inhibiting activity against HIV-1 protease the compound responsible was isolated and established as mangostin (Chen et al., 1996). Protostane triterpenes, e.g. garciosaterpenes A, B and C, obtained from methanol extracts of bark and stems of G. speciosa, showed anti-HIV-1 activity (Rukachaisirikul et al., 2003c). 

B. Lorenz, J. Leuck, D. Kohl, W. E. G. Muller and H. C. Schroeder (1997c). Anti-HIV-1 activity of inorganic polyphosphates. J. Acquir. Immun. Defic. Syndr. Hum. Retrovirol., 14, 110-118. 

Roush WR, Hall SE (1981) Studies on the total synthesis of chlorothricol-ide stereochemical aspects of the intramolecular Diels-Alder reactions of methyl undeca-2,8,10-trienoates. J Am Chem Soc 103 5200-5211 Rudler H, Denise B, Xu Y, Parlier A, Vaissermann J (2005) Bis(trimethylsilyl)-ketene acetals as C,0-dinucleophiles one-pot formation of polycyclic y-and 8-lactones from pyridines and pyrazines. Eur J Org Chem 3724-2744 Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise synthesis of anti-HIV-1 Active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-michael addition. J Org Chem 69 2760-2767... 

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