Publications

A series of N'(1),N'(3)-dialkyl-N'(1),N'(3)-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure-activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol.

Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors.

We report herein the SAR studies of a series of indole- and indolizine-glyoxylamides that demonstrate substantial in vitro anti-proliferative activities against cancer cell lines, including multidrug resistance (MDR) phenotypes. The in vitro cytotoxic effects have been demonstrated across a wide array of tumor types of various origins (e.g., breast, colon, uterine).

We report herein the SAR studies of a series of indole-imidazole compounds. that demonstrate substantial in vitro anti-proliferative activities against cancer cell lines, including multidrug resistance (MDR) phenotypes. The in vitro cytotoxic effects have been demonstrated across a wide array of tumor types, including hematologic and solid tumor cell lines of various origins (e.g., leukemia, breast, colon, and uterine).

We report the design and synthesis of bifunctional phospholipid conjugates, which contain a polymerizable acrylate group and a terminal linker, such as biotin or N-(epsilon-maleimidocaproyl (EMC), to facilitate bioconjugation reactions. The lipid conjugate can be used to generate a multifunctional substrate-supported phospholipid film that is further stabilized via in-situ photocopolymerization.

Phospholipid conjugates of mono- and disaccharides tethered with an n-decanyl spacer were efficiently synthesized via an improved reductive amination of deprotected omega-oxodecanyl beta-glycosides and phosphatidylethanolamines with or without alkenyl groups. The omega-oxodecanyl beta-glycosides were prepared by stereoselective glycosidation of glycosyl halides with 1, 10-decanediol followed by pyridinium dichromate oxidation. The acetyl groups of the omega-oxodecanyl beta-glycosides were removed with sodium methoxide prior to their conjugation with phosphatidylethanolamines.

An efficient synthesis of neoglycophospholipids with variable length alkyl spacer chains is described. Neoglycophospholipids tethered by alkyl chains of 3, 5, 7, 10, and 16 methylene units were synthesized in good overall yields in four steps. The key intermediates, omega-oxoalkyl glycopyranosides, were synthesized in two steps by glycosidation of chloro (or ethylthio) glycosides with a diol followed by oxidation of the remaining hydroxy group to an aldehyde functionality. Conjugation of the omega-glycoalkyl aldehyde with distearoylphosphatidylethanolamine via an improved reductive amination procedure significantly enhanced efficiency and yields with respect to those from traditional procedures. The amphiphilic properties of the neoglycophospholipids were characterized at the air-water interface. While the carbohydrate head group had relatively little effect, the length of the alkyl spacer profoundly influenced surface area-pressure isotherms.

Over several years sera were collected from 14 heterophil-positive students or patients who did not fulfill minimal hematologic criteria for infectious mononucleosis (I.M.) The specificity of these heterophil reactions for I.M. was investigated by determining antibodies to Epstein-Barr virus-determined antigens, i.e., to viral capsid antigens (VCA), early antigens (EA), and EBV-associated nuclear antigens (EBNA). On the basis of detectable anti-EA and/or the early absence and late emergence of anti-EBNA, four of these 14 individuals showed evidence of a current or very recent primary Epstein-Barr virus infection. The other ten patients showed antibody patterns indicative of Epstein-Barr virus infections in the past, and no firm conclusions could be drawn with regard to the specificity of their heterophil reactions. It was assumed, however, that some represented atypical clinical forms of EBV infection and that timing of specimen collection was a factor in explaining the paucity of Downey cells. In three patients, the absorbed heterophil-positive reactions persisted with little change in titer for at least 22 mo and thus might represent false-positive tests.

Over several years sera were collected from 14 heterophil-positive students or patients who did not fulfill minimal hematologic criteria for infectious mononucleosis (I.M.) The specificity of these heterophil reactions for I.M. was investigated by determining antibodies to Epstein-Barr virus-determined antigens, i.e., to viral capsid antigens (VCA), early antigens (EA), and EBV-associated nuclear antigens (EBNA). On the basis of detectable anti-EA and/or the early absence and late emergence of anti-EBNA, four of these 14 individuals showed evidence of a current or very recent primary Epstein-Barr virus infection. The other ten patients showed antibody patterns indicative of Epstein-Barr virus infections in the past, and no firm conclusions could be drawn with regard to the specificity of their heterophil reactions. It was assumed, however, that some represented atypical clinical forms of EBV infection and that timing of specimen collection was a factor in explaining the paucity of Downey cells. In three patients, the absorbed heterophil-positive reactions persisted with little change in titer for at least 22 mo and thus might represent false-positive tests.