Ognyan Petrov

Synthesis and antioxidant potential of novel synthetic benzophenone analogues.

Considering that oxidative stress is strongly implicated in the toxicity of chemotherapy, much effort is focused on the research of diverse antioxidants as protective agents. An efficient synthesis of three novel benzophenones containing 1,3-thiazol moiety (6a-c) is described. Their antioxidant power was evaluated in vitro and in three cell lines (the cancerous MCF7 and the non-cancerous hTERT-HME1 mammary cells, and the H9c2 cardiomyoblastic cells). One analogue 5-(2,5-dihydroxybenzoyl)-2(3H)-benzothiazolone (6c), displayed an important antioxidant activity, a low cytotoxicity, and could decrease reactive oxygen species production generated by tert-butyl hydroperoxide (tBHP) in all three cell lines. Interestingly, 6c was able to protect the non-cancerous cells against tBHP-induced death. Further studies are underway to determine its relevance as an adjuvant in oxidative stress inducing chemotherapy.

Selective Protein Hyperpolarization in Cell Lysates Using Targeted Dynamic Nuclear Polarization.

Nuclear magnetic resonance (NMR) spectroscopy has the intrinsic capabilities to investigate proteins in native environments. In general, however, NMR relies on non-natural protein purity and concentration to increase the desired signal over the background. We here report on the efficient and specific hyperpolarization of low amounts of a target protein in a large isotope-labeled background by combining dynamic nuclear polarization (DNP) and the selectivity of protein interactions. Using a biradical-labeled ligand, we were able to direct the hyperpolarization to the protein of interest, maintaining comparable signal enhancement with about 400-fold less radicals than conventionally used. We could selectively filter out our target protein directly from crude cell lysate obtained from only 8 mL of fully isotope-enriched cell culture. Our approach offers effective means to study proteins with atomic resolution in increasingly native concentrations and environments.

New heterocyclic chalcones. Part 6. Synthesis and cytotoxic activities of 5- or 6-(3-aryl- 2-propenoyl)-2(3H)-benzoxazolones

Abstract A number of chalcones bearing an oxazole cycle were synthesized by Claisen-Schmidt condensation of 5-acetyl-2(3H)-benzoxazolone or 6-acetyl-2(3H)-benzoxazolone and the appropriate aldehydes. The chalcones were evaluated for cytotoxic activity against several tumor cell lines – BV-173 (human B cell precursor leukemia), MCF-7 and MDA-MB-231 (human breast adenocarcinoma) using the MTT-dye reduction assay. The tested compounds exhibit concentration-dependent cytotoxic effects at micromolar concentrations. Exposure of the BV-173 tumor cell line to compound 3f results in strong mono- and oligonucleosomal fragmentation of genomic DNA, as evidenced by a ‘cell death detection’ ELISA kit, which unambiguously indicates that the induction of apoptosis is implicated in the cytotoxic mode of action of the tested compound.

A Convenient Synthesis of the New Histone Deacetylase Inhibitor Scriptaid

Histone deacetylase (HDAC) inhibitors represent a new promising class of anticancer agents, because of their ability to induce cell cycle arrest, differentiation and apoptosis of cancer cells.1–3 A number of products such as naturally occurring trichostatin A, trapoxins A and B, romidepsin as well as the synthetic derivatives suberoylanilide hydroxamic acid (SAHA), oxamflatin, belinostat, NVP-LAQ-824, valproic acid and MS-275 have been identified as HDAC inhibitors and have been shown to possess significant anticancer activity in several preclinical and clinical studies.4–12 Currently, two HDAC inhibitors – SAHA (Vorinostat or Zolinza R ©) and romidepsin (Istodax R ©), have been approved by the FDA for the treatment of cutaneous T-cell lymphoma in patients with progressive, persistent or recurrent disease.10,11 The therapeutic potential of HDAC inhibitors has spurred the synthesis of a large number of hydroxamic acids, cyclic peptides, short-chain fatty acids, benzamides and electrophilic ketones.3,4,10,12 Amongst them, hydroxamic acid derivatives have received the most attention because of their favorable pharmacokinetic profile and high activity against both hematological and solid tumors at well-tolerated doses.10,12 Scriptaid (3) was identified by Su et al.13 from a library of 16,320 compounds in a luciferase reporter assay. The compound is a hydroxamic acid and possesses the three pharmacophores common for this class of HDAC inhibitors, a hydroxamic acid zinc-binding group, a hydrophobic spacer, and a recognition cap group. The initial investigations of scriptaid showed that it is an effective HDAC inhibitor with low toxicity and high activity similar to those of SAHA.13 A recent in vitro study revealed that scriptaid provoked growth inhibition, cell cycle arrest and apoptosis in human endometrial cancer and ovarian cancer cells.14 An accumulation of acetylated H3 and H4 histone proteins was observed in these cell lines, confirming the effect of scriptaid as HDAC inhibitor.

AN EFFICIENT APPROACH TO THE IMIDAZO[5,1-c][1,4]BENZOTHIAZINE SKELETON. A NOVEL TRICYCLIC RING SYSTEM

Derivatives of a new type tricyclic system having a 1,4-benzothiazine skeleton are described. The reaction of l-(2-mercaptophenyl)-2//-imidazol-2-ones 2 with excess formaldehyde in acid medium resulted in the formation of 2,4-dihydro-lH-imidazo[5,l-c][l,4]benzothiazin-l-one 3. The starting compounds 2 were prepared by a modification of a previously described method of ring transformation of 3-(2-oxopropyI)-2(3//)-benzothiazoIones in reactions with primary amines.

Synthesis of 4-acetyl-2(3H)-benzothiazolone: Sulfur bioisostere of benzoxazolone allelochemicals

GRAPHICAL ABSTRACT ABSTRACT A multi-step methodology for the synthesis of 4-acetyl-2(3H)-benzothiazolone was developed in order to prepare a new biomimetic analogue of benzoxazolone allelochemicals. The compound was prepared from commercially available o-toluidine in 23% overall yield. The structure of 4-acethyl-2(3H)-benzothiazolone was confirmed by NMR spectroscopy and X-ray crystallography.

Dimethyl 2-{[2-(methoxycarbonyl)-1-(methoxycarbonylmethyl)pyrrol-4-yl]-methylene}propanedioate

The title compound, C(15)H(17)NO(8), is a pyrrole-ethene derivative with potential biological activity. Although a large part of the molecule is planar, there is no structural evidence for any conjugation push-pull effect across the ethylenic bond, which is usually observed for substituted ethylenes; pi-electron delocalization appears to be restricted to the 2-(methoxycarbonyl)pyrrole moiety.