Pamela Loreen Rossman

Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors.

DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented.

A comparison of the antibacterial and β-lactamase inhibiting properties of penam and (2,3)-β-methylenepenam derivatives : The discovery of a new β-lactamase inhibitor. Conformational requirements for penicillin antibacterial activity

Abstract The antibacterial potencies of 2a and 4 are shown to be diminished considerably from their penam analogues, penicillin G (1a) and mecillinam (3). Despite this, 2a is a substrate for bacterial β-lactamases, and compounds 6a, 8 and 10 were found to be β-lactamase inhibitors. Penicillin-binding protein (PBP) studies indicate that penicillin G and mecillinam have much greater affinity for these enzymes than the (2,3)-β-methylenepenam analogues. Based on a comparison of hydrolytic stabilities, it is proposed that the change in biological properties is due to conformational differences between the two types of penam nuclei. The cyclopropyl methylene of 2a and 4 blocks the side chain from forming an oxazolone with the β-lactam carbonyl. Hence, activation of the β-lactam is prevented and the molecules are rendered less active. We thus conclude that 19 is the biologically active conformation of penicillin antibacterials, and further suggest that the interaction of such antibiotics with their bacterial enzyme targets involves intermediates such as 25–27.

Pyrazolobenzodiazepines: Part I. Synthesis and SAR of a potent class of kinase inhibitors

A novel series of pyrazolobenzodiazepines 3 has been identified as potent inhibitors of cyclin-dependent kinase 2 (CDK2). Their synthesis and structure-activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK2 activity in vitro, and block cell cycle progression in human tumor cell lines. Further exploration has revealed that this class of compounds inhibits several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. Together, these properties suggest a compelling basis for their use as antitumor agents.

Synthesis and mechanistic studies of a ‘tetrazole-tethered” cephalosporin-quinolone hybrid

Abstract The synthesis and antibacterial activity of a novel ‘tetrazole-tethered’ cephalosporin-quinolone hybrid is described. The in vitro spectrum of 7 mirrored that of a third-generation cephalosporin. Quinolone-like activity was not observed. β-Lactamase-accelerated hydrolysis of 7 produced tetrazolylquinolone 12 which (via independent synthesis) proved to be a weak antibacterial and unable to form free quinolone.

(2,3)-(α-methylenepenams: Synthesis and in vitro activity

Abstract A series of α-methylene penicillins was synthesized and SAR were studied. The α-isomers were found to be chemically reactive and biologically active in contrast to the β-isomers. In addition, the α-isomers have broader spectrum of in vitro activity than the corresponding penicillins. Generally, the α-isomers are more active against gram-negative bacteria than the corresponding penicillins, but slightly weaker in potency towards gram-positive organisms.