Rosa Alvarez

Regiospecific Synthesis and Anti-Human Immunodeficiency Virus Activity of Novel 5-Substituted N-Alkylcarbamoyl and N,N-Dialkyl Carbamoyl 1,2,3-Triazole-TSAO Analogues

Several 5-N-alkyl and 5-N,N-dialkylcarbamoyl substituted analogues of the anti-human immunodeficiency virus (HIV) type 1 lead compound[1-[2‘,5’-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-5-(N,N-dimethylcarbamoyl)-1,2,3-triazole]-3‘-spiro-5“-(4”-amino-1“,2”-oxathiole-2“,2”-dioxide) have been prepared and evaluated as inhibitors of HIV-1 replication. A new regiospecific synthetic procedure is described. The compounds were prepared by cycloaddition of the appropriate glycosylazide to 2-oxo-alkylidentriphenyl-phosphoranes, followed by treatment with primary or secondary amines, to yield, exclusively, 5-substituted 1,2,3-triazole-TSAO analogues. Several 5-substituted 1,2,3-triazole-TSAO derivatives proved to be potent inhibitors of HIV-1 replication with higher antiviral selectivity than that of the parent TSAO prototype.

Hit to Lead Evaluation of 1,2,3-Triazolo[4,5-B]Pyridines as Pim Kinase Inhibitors.

PIM kinases have become targets of interest due to their association with biochemical mechanisms affecting survival, proliferation and cytokine production. 1,2,3-Triazolo[4,5-b]pyridines were identified as PIM inhibitors applying a scaffold hopping approach. Initial exploration around this scaffold and X-ray crystallographic data are hereby described.

Novel Approach for Chemotype Hopping Based on Annotated Databases of Chemically Feasible Fragments and a Prospective Case Study: New Melanin Concentrating Hormone Antagonists

A novel strategy for chemotype hopping, based on annotated databases of chemically feasible fragments and their oriented functionalization, is presented. A three-dimensional (3D) similarity analysis of project-oriented functionalized scaffolds provides a prioritized proposal for synthesis with the most appropriate linkers and optimal regiochemistry on R-groups. This strategy maximizes the potential of proprietary and commercially available compounds. A retrospective and prospective case study, on melanin concentrating hormone (MCH) antagonists, showing the impact on the drug discovery process of this new strategy by maintaining primary activity and improving key ADME/Tox property while enhancing intellectual property (IP) position is demonstrated.

Hiv-1 Specific Reverse Transcriptase Inhibitors: why are Tsao-Nucleosides so Unique?

1. INTRODUCTION AIDS will still be one of the most important challenges for the Scientific Community in the approaching new century. Since the identification, in 1983-84,1,2 of human immunodeficiency virus (HIV) as the etiological agent of AIDS, significant progress has been made in the treatment of HIV-infected patients. This has been in part due to the discovery and clinical use of an increasing number of anti-HIV drugs. However, while highly active antiretroviral therapy (HAART)3 approaches have reduced the morbidity and mortality, the intertwined problems of drug induced viral resistance, poor compliance with complex regimens and therapy failure continue. Therefore, there remains a pressing need for the development of new antiviral agents that can be used not only as first line therapeutic candidates, but also in the antiretroviral-experienced patient population.

TSAO Derivatives: Highly Specific Inhibitors of Human Immunodeficiency Virus Type-1 (HIV-1) Replication

Abstract TSAO derivatives represent a unique class of nucleosides that are specifically targeted at HIV-1 RT. This overview is focussed on the chemical synthesis, the conformational studies, the antiviral and metabolic properties of TSAO derivatives, as well as their mechanism of antiviral action and the molecular basis of the rapid selection of resistant HIV-1 strains that emerge in cell culture in the presence of TSAO derivatives.

SYNTHESIS AND ANTI-HIV-1 ACTIVITY OF 4- AND 5-SUBSTITUTED 1,2,3-TRIAZOLE-TSAO DERIVATIVES

Abstract Several 4- or 5-monosubstituted and 4,5-disubstituted 1,2,3-triazole analogues of the anti-HIV-1 lead compound [1-[2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]thymine]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) (TSAO-T) have been prepared and evaluated for their inhibitory effect against HIV-1-induced cytopathicity.

Novel 3'-spiro nucleoside analogues of TSAO-T. Part II. A comparative study based on NMR conformational analysis in solution and theoretical calculations.

The structures of two novel 3′-spiro nucleosides analogues of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-m3T, in solution, as derived from NMR spectroscopy are described. In these TSAO analogues the spiro amino oxathioledioxide moiety has been replaced by spiro amino oxazolone or spiro amino oxathiazoledioxide moieties. A comparative study based on theoretical calculations of the hydrophobicity, the solvation free energies and molecular electrostatic potentials (MEP) of the three compounds is also described. No significant conformational differences were detected in solution between TSAO-m3T and its analogues that might account for the differencesobserved in their inhibitory activity against HIV-1 RT. The calculated hydrophobicity (log P) values, dipole moments and the electrostatic contributions to the solvation free energies of the three spiro ring systems were also similar. However, the differences found in the calculated MEPs of the spiro systems between TSAO-m3T and its analogues suggest that the different electrostatic surroundings of the 4″-amino group of the spiro moiety in the analogues may be responsible for a detrimental electrostatic interaction of the spiro rings with the Glu-B138 of RT.

Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies.

The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours.

Synthesis, NMR studies and theoretical calculations of novel 3-spiro-branched ribofuranoses

Abstract Novel spiro-branched sugar derivatives bearing a spiro-5′-(4′-amino-2′-oxazolone) or a spiro-5′-(4′-amino-1′,2′,3′-oxathiazole-2′,2′-dioxide) rings at position-3 of the sugar moiety have been prepared. The synthesis has been achieved by a one-pot procedure from a conveniently protected sugar cyanohydrin derivative by reaction with chlorosulfonyl isocyanate or sulfamoyl chloride, respectively. The tautomeric preference in solution of these novel 3-spiro sugars are described as derived from NMR spectroscopy. Also a comparative theoretical study, by ab-initio methods, of the steric and electronic properties of the spiro rings present in these sugar derivatives has been performed.

Novel Tsao Derivatives. Synthesis and Anti-HIV-1 Activity of Allofuranosyl-TSAO-T Analogues ‡

Abstract Novel TSAO-T analogues, in which the ribofuranosyl moiety has been replaced by an hexofuranosyl sugar moiety, have been prepared and evaluated for their inhibitory effect on HIV-1 replication in cell culture. In contrast to the prototype compound TSAO-T, the hexofuranosyl derivatives proved not active at subtoxic concentrations. ‡Dedicated to Dr. Yoshihisa Mizuno on the occasion of his 74th birthday.