Mariana Gerova

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.

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.

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.

Synthesis of a new polycyclic heterocyclic ring system. Part III. Benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-diones

Abstract A series of novel tricyclic benzoxazepines with fused imidazolone ring was prepared in five steps starting from the corresponding benzoxazolones 1–3. The key to the reported synthetic approach is transformation of 3-(2-oxopropyl)-2(3H)-benzoxazolones 4–6 to 1-(2-hydroxyphenyl)-4-methyl-1,3-dihydro-2H-imidazol-2-ones 7–12, and their subsequent conversion to the phenoxyacetic acids 19–24, which were finally acylated in polyphosphoric acid to form the oxazepine ring.

(E)-3-Methyl-6-(3-oxo-3-(thiophen-2-yl)-1-propenyl)-2 (3H)-benzothiazolone

The title compound, (E)-3-methyl-6-(3-oxo-3-(thiophen-2-yl)-1-propenyl)-2(3H)-benzothiazolone, was synthesized by Claisen-Schmidt condensation of 3-methyl-2(3H)-benzothiazolone-6-carbaldehyde with 2-acetylthiophene in 94% yield. The structure of the target compound was confirmed using 1H-NMR, 13C-NMR, IR, MS, and elemental analysis.

(E)-3-Methyl-6-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-2(3H)-benzothiazolone

The title compound, (E)-3-methyl-6-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-2(3H)-benzothiazolone, was synthesized by both an acid- and base-catalyzed aldol condensation of 3-methyl-6-acetyl-2(3H)-benzothiazolone and 3,4,5-trimethoxyacetophenone. The structure of the target compound was confirmed using 1H-NMR, 13C-NMR, IR, MS, and elemental analysis.

6-[(4-Chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-3-methyl-2(3H)-benzoxazolone

A new hybrid molecule containing a triazole and a benzoxazolone ring was synthesized. The structure of 6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl) methyl]-3-methyl-2(3H)-benzoxazolone was confirmed by IR, 1H-, 13C-NMR, MS and elemental analysis.

3-(2-Oxopropyl)-2(3H)-benzoxazolone

The title compound is an important intermediate for the preparation of 3,4- and 3,4,5-substituted 1-(2-hydroxy-phenyl)imidazolin-2-ones [1,2] and 6-methyl-4-(2-hydroxyphenyl)-1,2,4-triazin-3-ones [3].[...]