Amarendra B. Mikkilineni

Novel water soluble phosphate prodrugs of taxol® possessing in vivo antitumor activity☆

Abstract Synthesis and biological evaluation of novel taxol derivatives having a phosphonoxyphenylpropionate ester group at the 2′-position or at the 7-position of taxol are described. These were found to have much improved water solubility and both were found to generate taxol upon exposure to alkaline phosphatase. A particular derivative, 7-phosphonoxyphenylpropionate of taxol 3b exhibited antitumor activity comparable to that of taxol against the ip/ip M109 murine tumor model.

Synthesis and antitumor evaluation of 2′-oxycarbonylpaclitaxels (paclitaxel-2′-carbonates)

Abstract A number of 2′-oxycarbonylpaclitaxels (paclitaxel-2′-carbonates) 3 have been prepared and evaluated for their cytotoxicity and in vivo antitumor activity. Most of these paclitaxel-2′-carbonates were found to exhibit in vivo antitumor activity in the i.p. M109 murine tumor model system, comparable to that of the parent drug.

Novel, water-soluble phosphate derivatives of 2′-ethoxy carbonylpaclitaxel as potential prodrugs of paclitaxel: Synthesis and antitumor evaluation

Abstract Three new phosphate derivatives of paclitaxel-2′-ethylcarbonate 4a, 4b, and 4c, have been synthesized and evaluated for in vivo antitumor activity. All were soluble in water and two derivatives 4a and 4b were found to exhibit in vivo antitumor activity, comparable to paclitaxel in the M109 murine tumor model.

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

BMS-196085: A potent and selective full agonist of the human β3 adrenergic receptor

A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.

Synthesis of phenoxyacetyl-N-(hydroxydioxocyclobutenyl)cycloserines

Abstract The synthesis and antibacterial activity of a potential antibiotic, phenoxyacetyl-(L)-cycloserine activated by a cyclobutenedione moiety, is described.

Synthesis of α-(S)-acylamino-N-(hydroxydioxocyclobutenyl)-β-lactams as potential antibiotics

Abstract Monocyclic β-lactams 6 activated by a hydroxycyclobutenedione moiety have been prepared as potential antibacterial agents from the natural amino acids, (L)-serine and (L)-threonine. These β-lactams were devoid of useful antibacterial activity.

Synthesis of α-(S)- acylamino-n-(hydroxydioxocyclobutenyl)- γ-lactams

Abstract Monocyclic γ - lactams 2 , activated by a hydroxycyclobutenedione moiety have been prepared from (L)-N t Boc-glutamine, as potential antibacterial agents.