SCH 529074

SEM studies on acanthocephalan parasite, Echinorhynchus veli infecting the fish Synaptura orientalis (Bl & Sch, 1801).[Pubmed:28316390]

J Parasit Dis. 2017 Mar;41(1):71-75.

Echinorhynchus veli (George and Nadakal, 1978), an acanthocephalid worm infesting the estuarine flat fish, Synaptura orientalis, was collected from the Veli lake, Kerala. The parasite was recovered from the intestine of the host fish. The detailed surface morphology was studied with the help of scanning electron microscope. The study revealed a cylindrical, medially swollen proboscis with a flat apex, backward directed hooks, each with smooth surface, broad base, pointed tip and an epidermal elevation at the point of insertion. A pair of sensory pits was seen at the base of the proboscis. The neck was well developed with densely packed epidermal micropores. Paired sensory pits were seen at the base of the neck and a collar between it and the trunk. The epidermis of the trunk has microtriches and micropores. The female genital pore was circular, and terminal in an elevated orifice. In male, the copulatory bursa was directed ventrally, with well-defined rim and several sensory papillae.

Structural Determination of (-)-SCH 64874 and Hirsutellomycin by Semisynthesis.[Pubmed:27966974]

J Org Chem. 2017 Jan 6;82(1):353-371.

The structure of a C2-symmetric epidithiodiketopiperazine alkaloid, SCH 64874, was determined by semisynthesis. The relative stereochemistry of the beta-hydroxy carboxylic acid chain having three chiral centers was determined by comparison of the NMR data of the four possible diastereomeric beta-hydroxy carboxylic acid fragments with those of SCH 64874. Condensation of the (-)-deacetylaranotin core with two enantiomeric beta-hydroxy carboxylic acids revealed the relative stereochemistry of SCH 64874. The relative stereochemistry of the beta-keto carboxylic acid chain of the analogous alkaloid hirsutellomycin was determined in a stepwise manner. The C4'-C6' syn relationships were predicted by comparing the NMR data of the corresponding ester fragments with that of hirsutellomycin. The relative stereochemistry of the whole molecule, including the epimerizable C2' stereocenter, was determined by introduction of four possible side chains into the bisdethiodi(methylthio)deacetylaranotin core. We found that the stereochemistry of C2' converged with that of the thermodynamically stable form influenced by the core structure.

SCH 79797, a selective PAR1 antagonist, protects against ischemia/reperfusion-induced arrhythmias in the rat hearts.[Pubmed:27906419]

Eur Rev Med Pharmacol Sci. 2016 Nov;20(22):4796-4800.

OBJECTIVE: Thrombin is implicated in the genesis of arrhythmias and activation of thrombin receptors exacerbated ventricular arrhythmias following coronary artery ligation. The present study was designed to investigate the possible protective effect of the protease-activated receptor-1 antagonist, SCH79797 against ischemia and reperfusion arrhythmias in the rat heart. MATERIALS AND METHODS: Healthy male Wistar rats (250-350 g) were anesthetized with urethane. Coronary artery ligation was performed for 5 minutes followed by 10 minutes reperfusion. Rhythm disturbances were monitored throughout the ischemia and reperfusion periods. Drugs injected were SCH79797 dihydrochloride (6.25, 12.5, 25 and 100 microg/kg), glibenclamide (5 mg/kg) and N-nitro L-arginine methyl-ester hydrochloride (25 mg/kg). The control group was injected with dimethylsulfoxide (0.1 ml). RESULTS: SCH79797 dihydrochloride reduced the number of premature contraction, prevalence and duration of ventricular tachycardia, prevalence and duration of ventricular fibrillation during both the ischemic and reperfusion periods in a dose-dependent manner. There is a trend for N-nitro L-arginine methyl-ester hydrochloride to increase all parameters of arrhythmias in SCH79797 dihydrochloride (25 microg/kg) treated rats, but glibenclamide (5 mg/kg) significantly (p < 0.05) increased these parameters. CONCLUSIONS: SCH79797 dihydrochloride induced an antiarrhythmic effect in the anesthetized rat. This protective effect could possibly be mediated by activation of nitric oxide synthase and/or of ATP-sensitive potassium channels.

Design and synthesis of water soluble beta-aminosulfone analogues of SCH 900229 as gamma-secretase inhibitors.[Pubmed:27836402]

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5836-5841.

In this paper we describe our strategy to improve the aqueous solubility of SCH 900229, a potent PS1-selective gamma-secretase inhibitor for the treatment of Alzheimer's disease. Incorporation of ionizable amino groups into the side chain terminal generates water soluble beta-aminosulfone analogues of SCH 900229 that maintain robust in vitro potency and in vivo efficacy.

Translational approaches targeting the p53 pathway for anti-cancer therapy.[Pubmed:21718309]

Br J Pharmacol. 2012 Jan;165(2):328-44.

The p53 tumour suppressor blocks cancer development by triggering apoptosis or cellular senescence in response to oncogenic stress or DNA damage. Consequently, the p53 signalling pathway is virtually always inactivated in human cancer cells. This unifying feature has commenced tremendous efforts to develop p53-based anti-cancer therapies. Different strategies exist that are adapted to the mechanisms of p53 inactivation. In p53-mutated tumours, delivery of wild-type p53 by adenovirus-based gene therapy is now practised in China. Also, remarkable progress has been made in the development of p53-binding drugs that can rescue and reactivate the function of mutant or misfolded p53. Other biologic approaches include the development of oncolytic viruses that are designed to specifically replicate in and kill p53-defective cells. Inactivation of wt-p53 frequently results from dysregulation of MDM2, an E3 ligase that regulates p53 levels. Small-molecule drugs that inhibit the interaction of MDM2 and p53 and block p53 degradation are currently tested in clinical trials. This survey highlights the recent developments that attempt to modulate the function of p53 and outlines strategies that are being investigated for pharmacological intervention in the p53 pathway.

SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53.[Pubmed:20124408]

J Biol Chem. 2010 Apr 2;285(14):10198-212.

Abrogation of p53 function occurs in almost all human cancers, with more than 50% of cancers harboring inactivating mutations in p53 itself. Mutation of p53 is indicative of highly aggressive cancers and poor prognosis. The vast majority of mutations in p53 occur in its core DNA binding domain (DBD) and result in inactivation of p53 by reducing its thermodynamic stability at physiological temperature. Here, we report a small molecule, SCH529074, that binds specifically to the p53 DBD in a saturable manner with an affinity of 1-2 microm. Binding restores wild type function to many oncogenic mutant forms of p53. This small molecule reactivates mutant p53 by acting as a chaperone, in a manner similar to that previously reported for the peptide CDB3. Binding of SCH529074 to the p53 DBD is specifically displaced by an oligonucleotide with a sequence derived from the p53-response element. In addition to reactivating mutant p53, SCH529074 binding inhibits ubiquitination of p53 by HDM2. We have also developed a novel variant of p53 by changing a single amino acid in the core domain of p53 (N268R), which abolishes binding of SCH529074. This amino acid change also inhibits HDM2-mediated ubiquitination of p53. Our novel findings indicate that through its interaction with p53 DBD, SCH529074 restores DNA binding activity to mutant p53 and inhibits HDM2-mediated ubiquitination.