Balu Balasubramanian

Non-camptothecin topoisomerase I active compounds as potential anticancer agents

The success of two camptothecin analogues against human cancers has prompted pharmaceutical companies and academic laboratories to not only initiate camptothecin analogue programs of their own, but also to either screen for or to rationally design novel topoisomerase (topo) I active agents. The primary focus of this review is on those agents that most closely mimic the actions of camptothecin, the prototype topo I acting agent. Indolocarbazoles are the most exploited and advanced chemotype, being led by NB-506 and J-107088, both of which have entered Phase I/II clinical evaluations by Merck/Banyu. Kyowa Hakko Kogyo, while expanding the K252a/staurosporine series, identified topo I active agents but continued to the clinic with the protein kinase inhibitor UCN-01. Approximately 100 non-proprietary indolocarbazoles have been described in the literature by a consortium of academic scientists working in conjunction with scientists at Aventis and Novartis. Their intent appears to be more academic than commercial and this association has now ended. An academic group, through an agreement with Avax Technologies is commercially exploring benzimidazoles, terbenzimidazoles, coralyne and protoberberines. Indenoisoquinoline NSC 314622 and anthracenyl-amino acid conjugate NU/ICRF 505 are interesting and novel structures that have not yet progressed to the clinic. The naphthacenedione family includes saintopin, which was discovered by Kyowa Hakko Kogyo. This company appears to be focusing on UCE6. Other agents include nogalamycin, dexniguldipine HCl (B859-35), ecteinascidin 743 (Et 743) and phthalascidin (Pt 650). 2280-DTI and 2890-DTI may be true catalytic inhibitors of topo I. Only NB-506, J-107088, dexniguldipine and Et 743 have undergone or are presently undergoing Phase I/II clinical evaluation with little information coming forth, except for Et 743, which is yielding responses against sarcomas.

Sordaricin antifungal agents

Compounds based on sordaricin were prepared via organometallic addition onto a fully protected sordaricin aldehyde. The fungal growth inhibition profiles for these compounds were established and the results are presented here. The synthesis of homologated sordaricin as well as ether and ester derivatives is presented, and structural rearrangement products upon oxidation. These compounds were evaluated as agents to inhibit fungal growth.

Sordarin oxazepine derivatives as potent antifungal agents

The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.

A Synthesis of N-Bridged 5,6-Bicylic Pyridines via A Mild Cyclodehydration Using the Burgess Reagent and Discovery of A Novel Carbamylsulfonylation Reaction

Cyclodehydration using the Burgess reagent provided a novel approach toward the synthesis of N-bridged 5,6-bicylic pyridines including pyrolo-, imidazo-, and triazolopyridines under mild and neutral conditions. The methodology tolerates acid-sensitive functional groups. A novel addition product was observed between the resulting pyrrolo- or imidazopyridine and an additional equivalent of the Burgess reagent, producing the corresponding sulfonylcarbamate adduct.

Oxime derivatives of sordaricin as potent antifungal agents

Oxime derivatives of the sordarin aglycone have been identified as potent antifungal agents. The in vitro spectrum of activity includes coverage against Candida albicans and Candida glabrata with MICs as low as 0.06 microg/mL. The antifungal activity was established to be exquisitely sensitive to the spatial orientation of the lipophilic side chains.

Mild deprotection of 2-(trimethylsilyl)ethyl esters

Abstract A method for the deprotection of 2-(trimethylsilyl)ethyl (TMSE) esters is described. Treatment of carboxylic esters with NaH in DMF cleanly produces the deprotected acid after extractive work-up. This method can be applied to sterically-hindered substrates as well as esters containing fluoride-labile functionality. A tandem alkylation/ester deprotection procedure is also presented.

Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development

Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.

Core-modified sordaricin derivatives: synthesis and antifungal activity.

Core-modified sordaricin derivatives were prepared via biotransformation followed by chemical modification and tested for antifungal activity. The antifungal activity proved to be very sensitive to modifications in the sterics and/or lipophilicity of the diterpene skeleton. Introduction of polar groups such as hydroxyl in the diterpene core results in loss of potency while small and lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.

Synthesis and characterization of tritium labeled N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-sulfamoylbenzamide.

N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-sulfamoylbenzamide is a potent C-C chemokine receptor 1 (CCR1) antagonist. The compound, possessing benzamide functionality, successfully underwent tritium/hydrogen (T/H) exchange with an organoiridium catalyst (Crabtrees catalyst). The labeling pattern in the product was studied with liquid chromatography-mass spectrometry, time-of-flight mass spectrometry, and (3) H-NMR. Overall, multiple labeled species were identified. In addition to the anticipated incorporation of tritium in the benzamide moiety, tritium labeling was observed in the valine portion of the molecule including substitution at its chiral carbon. Using authentic standards, liquid chromatography analysis of the labeled compound showed complete retention of stereochemical configuration.