Biomedical subjects
Publications and source records attributed to Tony Y Zhang.
PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.
A series of 2-dialkylphosphino-2'-alkoxy-1,1'-binaphthyl ligands (6a-c and 8a-c) have been prepared conveniently by a lithium-initiated ring-opening reaction of dinaphthofuran, followed by selective phosphorylation. These compounds displayed a remarkable air and moisture stability, both in solid form and in solution. Application of these phosphine ligands in palladium-catalyzed C-N bond forming reactions revealed the crucial roles of the steric bulk of the substituents on the phosphorus atom governing the catalytic activity. Specifically, 2-di-tert-butylphosphino-2'-isopropoxy-1,1'-binaphthyl (8b) proved to be the most effective for the aminations of aryl halides with primary amines, while the less bulky 2-dicyclohexyl-2'-methoxy-1,1'-binaphthyl (6a) was more effective for the aminations with secondary amines. The steric and electronic effects of the ligands were analyzed to account for these observations.
[reaction: see text] Oxidation of alkynes to alpha-dicarbonyl derivatives through a convenient one-pot procedure via a Brønsted acid-promoted "hydration" and a DMSO-based oxidation sequence has been achieved in high yields. The scope and limitations of the reaction have also been investigated.
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The synthesis of the peroxime proliferator activated receptor (PPAR) alpha,gamma-agonist (1) was accomplished with high enantio- and diastereoselectivity by employing an asymmetric hydrogenation strategy, of an alpha-alkoxy cinnamic acid derivative, to set the C-2 chiral center. A diastereospecific S(N)2 displacement under mild basic conditions established the C-10 stereochemistry without any detectable racemization of the two epimerizable chiral centers.
Herein we describe a series of potent and selective PPARgamma agonists with moderate PPARalpha affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.
Cryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d x 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr [a pgp (+) MDR tumor]: 0%T/C, 3.2 LK; Mam 16/C/Adr [a pgp (-) MDR tumor]: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 [a pgp (+) MDR tumor]: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.
Five 1,3-disubstituted imidazolium salts were synthesized. Their Heck reaction activities were evaluated. A convenient, efficient and high yielding procedure based on these compounds for the arylation of olefins was developed. Heck reactions mediated by these palladium-N-heterocyclic carbene complexes were conducted under air and even in the presence of several common oxidants.
A highly effective, easy to handle and environmentally benign process for palladium mediated Suzuki cross-coupling was developed. By utilizing a solid support based NHC-palladium catalyst, cross couplings of aryl bromides with phenylboronic acid were achieved in neat water under air. A high ratio of substrate to catalyst was also realized.