Subas M. Sakya

Preparation and inverse electron demand Diels-Alder reactions of 3-methoxy-6-methylthio-1,2,4,5-tetrazine

The selective preparation of 3-methoxy-6-methylthio-1,2,4,5-tetrazine (2) and 3,6-dimethoxy-1,2,4,5-tetrazine (3) from 3,6-bis(methylthio)-1,2,4,5-tetrazine (1) is described. A preliminary investigation into the participation of 2 in [4+2] cycloaddition reactions with electron rich and neutral dienophiles along with the resulting regioselective formation of the products (5) are discussed.

Synthesis and preliminary evaluation of (+)-CBI-indole2: an enhanced functional analog of (+)-CC-1065

Abstract The synthesis and comparative preliminary evaluation of (+)-CBI-indole 2 ( 3 ) are detailed in efforts that further demonstrate a direct relationship between the chemical stability of the agents and their biological potency/DNA alkylation intensity.

Preparation of novel tricyclic diazo carbapenems: Application of inverse electron demand Diels-Alder reactions of 3,6-bis(methylthio)-1,2,4,5-tetrazine

Abstract The syntheses of novel tricyclic diazo carbapenem precursor 17 , and the deprotected carbapenems 2 and 3 are described. The construction of the tricyclic carbapenem was accomplished by an intramolecular nucleophilic substitution of the diazine sulfone 16 which was obtained from an inverse electron demand Diels-Alder reaction of the alkynyl azetidinone 13 with 3,6-bis(methylthio)-1,2,4,5-tetrazine (4) .

Stereoselective synthesis of spiropiperidines as BACE-1 aspartyl protease inhibitors via late stage N-arylation of a 1,8-diazaspiro[4.5]dec-3-en-2-one pharmacophore.

A stereoselective synthesis of spiropiperidine compounds, exemplified by compound 1, was developed, which was based upon the late stage N-arylation of a 1,8-diazaspiro[4.5]dec-3-en-2-one pharmacophore. Previously, compound 1 was prepared in low overall yield from piperidinone 2 via the Strecker reaction. A new route was developed, which employed the stereospecific Corey-Link reaction of an enantiomerically pure trichloromethylcarbinol to give a template compound amenable to late stage N-arylation.

Peptidic prodrugs of novel aminomethyl-THF 1β-methylcarbapenems

Abstract Peptidic prodrugs of the five most active aminomethyl-THF 1β-methylcarbapenems were synthesized. Of these, only L-amino acid derivatives from 1a demonstrated an improved oral activity. These results indicate that the L-amino acid derivatives from 1a are orally absorbed most likely through the dipeptide and tripeptide transport mechanism.

Synthesis and structure-activity relationships of novel THF 1β-methylcarbapenems II

Abstract A series of twelve highly active aminomethyl-THF 1β-methylcarbapenems 3a-1 were synthesized. Of these, carbapenems 3a-f demonstrated a spectrum of antimicrobial activity comparable to those of imipenem and meropenem with the exception of only moderate anti-pseudomonal activity. Most importantly, they demonstrated moderate intrinsic oral activity against an E. coli infection in mice.

Synthesis and structure-activity relationships of some novel oxetane carbapenems

Six disubstituted oxetane carbapenems were synthesized and their antibacterial profile compared with the lead amino methyl THF carbapenem as well as imipenem. The oxetane carbapenems had comparable or less activity against the Gram(−) bacteria and had reduced activity against Gram(+) bacteria in comparison with imipenem and the THF carbapenem CL 191, 121, but were highly stable to hydrolysis by hog kidney dehydropeptidase (DHP).

Mono and bis double ester prodrugs of novel aminomethyl-THF 1β-methylcarbapenems

Mono and bis double ester prodrugs of aminomethyl THF 1β-methylcarbapenems 1 were synthesized. Mono double ester derivatives (2, 4 and 7) did not demonstrate significantly improved oral activity due to the presence of the charged species. However, bis double ester derivatives (3 and 5) demonstrated enhanced oral activity.