Robert Vince

Glyoxalase inhibitors as potential anticancer agents.

Abstract A study of a series of S-alkylglutathiones as inhibitors of the enzyme, glyoxalase I, revealed that a non-polar region exists on the enzyme which plays an important role in the formation of an enzyme-inhibitor complex. The amount of inhibition of glyoxalase increases as the alkyl chain is lengthened from methyl to n-octyl. By taking advantage of the non-polar region of the enzyme, compounds have been prepared which are 435 times more active than the previously reported S-methylglutathione.

SYNTHESIS AND ANTIVIRAL EVALUATION OF CARBOCYCLIC ANALOGS OF RIBOFURANOSIDES OF 2‐AMINO‐6‐SUBSTITUTED‐PURINES AND OF 2‐AMINO‐6‐SUBSTITUTED‐8‐AZAPURINES

Carbocyclic analogues of lyxofuranosides of 2-amino-6-substituted-purines and 2-amino-6-substituted-8-azapurines were synthesized from (+/-)-(1 alpha, 2 alpha, 3 alpha, 5 alpha)-3-amino-5- (hydroxymethyl)-1,2-cyclopentanediol (2) and 2-amino-4,6-dichloropyrimidine (3). The 2-amino-6-chloropurine (8 and 11), the 2,6-diaminopurine (10 and 13), as well as the guanine (9) and 8-azaguanine (12) derivatives were all constructed from the key intermediate (+/-)-(1 alpha, 2 alpha, 3 alpha, 5 alpha)- 3-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]-5-(hydroxymethyl)-1,2- cyclopentanediol (7) by using established methodology. Compounds 8-13 were evaluated for both antitumor and antiviral activity. None of these materials exhibited appreciable activity against P-388 mouse leukemia cells in vitro. All of these analogues were investigated for activity versus herpes simplex virus type 1 (HSV-1) and influenza virus (IV-A), as well as the human immunodeficiency virus (HIV). Against HSV-1, only compound 9, the carbocyclic analogue of the lyxofuranoside of guanine, exhibited significant activity, yielding a virus rating (VR) of 2.1. The corresponding 2,6-diamino compound (10) demonstrated marginal activity, VR = 0.6, against that virus. The test compounds failed to exhibit inhibition of either IV-A or HIV. Additionally, 9 was tested against human cytomegalovirus (HCMV) and was found to display definite activity at concentrations as low as 32 microM.

Design, synthesis and biological evaluation of glutathione peptidomimetics as components of anti-Parkinson prodrugs.

Plethoras of CNS-active drugs fail to effect their pharmacologic response due to their in vivo inability to cross the blood-brain barrier (BBB). The classical prodrug approach to overcome this frailty involves lipophilic derivatives of the polar drug, but we herein report a novel approach by which endogenous transporters at BBB are exploited for brain drug delivery. The crucial role played by glutathione in pathogenesis of Parkinsons and the presence of its influx transporters at the basolateral membrane of BBB served as the basis for our anti-Parkinson prodrug design strategy. A metabolically stable analogue of glutathione is used as a carrier for delivery of dopamine and adamantamine. An account of successful syntheses of these prodrugs along with their transport characteristics and stability determination is discussed.

(±) 4β-amino-2α,3α-dihydroxy-1β-cyclopentanemethanol hydrochloride. Carbocyclic ribofuranosylamine for the synthesis of carbocyclic nucleosides.

Abstract Carbocyclic ribofuranosylamine, a key intermediate for the synthesis of carbocyclic ribonucleosides, was synthesized by a facile route from the lactam, 2-azabicyclo[2.2.1]hept5-ene-3-one.

3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase

Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (INIs). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure-activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.

Inhibition of Glyoxalase I: The First Low-Nanomolar Tight-Binding Inhibitors

A series of rational modifications to the structure of known S-(N-aryl-N-hydroxycarbamoyl)glutathione-based glyoxalase I inhibitors culminated in the discovery of the first single-digit nanomolar inhibitor. This study makes available key information about possible means to address the issues of metabolic instability, low potency, and synthetic complexicity that have plagued the area of glyoxalase I inhibition. Knowledge garnered from this study has implications in the design of inhibitors with higher conformational definition and lower peptidic character.

The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus.

C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C-6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site.

Cyclohexenyl nucleosides: Synthesis of cis-4-(9H-purin-9-yl)-2-cyclohexenylcarbinols

Abstract Syntheses of the title compounds were accomplished in 6–7 steps, starting from cyclohexadiene and chlorosulphonyl isocyanate. The key step of the strategy involves a palladium coupling of cyclohexenyl dicarbonate 8 with either 6-chloropurine or 2-amino-6-chloropurine.

Pharmacophore and structure–activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase

Rational design of dually active inhibitors against human immunodeficiency virus (HIV) reverse transcriptase (RT) and integrase (IN) has proved viable with 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) type of non-nucleoside RT inhibitors (NNRTIs). To establish the pharmacophore and study the structure-activity relationships (SAR) of integrase inhibition within a previously disclosed RT/IN dual inhibitor scaffold, new analogues featuring substitution at different sites of the HEPT ring were designed and synthesized. These studies have revealed an IN inhibition pharmacophore that is merged with the known RT pharmacophore through a shared C-6 benzyl group. Further SAR also demonstrated that optimal IN inhibition within our dual inhibitor scaffold requires a regiospecific (N-1) diketoacid (DKA)-carrying pendant with a certain length.

Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: Introducing a diketoacid functionality into delavirdine

Cost and toxicity problems associated with highly active antiretroviral therapy (HAART) in HIV/AIDS treatment could be alleviated by using designed multiple ligands (DMLs). Dual inhibitors of HIV reverse transcriptase (RT) and integrase (IN) were rationally designed by introducing a diketoacid (DKA) functionality into the tolerant C-5 site of RT inhibitor delavirdine. The resulting compounds all demonstrate good activity against both RT and IN in enzymatic assays and HIV in cell-based assay, whereas their C-7 regioisomers are all inactive in these assays. Balanced activities were observed with C-3 halogenated inhibitors.