Gilbert Kirsch

Preparation of thieno[2,3-b]pyrroles starting from ketene-N,S-acetals

Thieno[2,3-b]pyrroles 4 can easily be synthesised in two different ways by using phenyl isothiocyanate and activated methylene compounds. The priority of the formation of the thiophene or pyrrole ring is investigated.

Formylation, dicyanovinylation and tricyanovinylation of 5-alkoxy- and 5-amino- substituted 2,2'-bithiophenes

Abstract Several donor–acceptor-substituted bithiophenes were synthesized by functionalization of the corresponding 5-alkoxy- or 5-aminobithiophenes 1 by different methods: Vilsmeier formylation, metalation followed by reaction with DMF, direct tricyanovinylation reaction using TCNE or Knoevenagel condensation starting from the corresponding 5-formyl- derivatives of 1 .

A rapid access to coumarin derivatives (using Vilsmeier–Haack and Suzuki cross-coupling reactions)

Abstract A four-step preparation of compounds containing a coumarinic moiety is presented. This synthesis involves notably a Suzuki cross-coupling reaction (performed in aqueous media) and a ring closure by formation of δ-lactone.

Palladium-catalyzed amination and cyclization to heteroannellated indoles and carbazoles

Abstract New ortho-bromodiarylamines in the benzo[b]thiophene series were prepared by palladium-catalyzed amination, either in the benzene or in the thiophene ring. These were submitted to palladium-catalyzed cyclization, under different required conditions, to give several differently substituted thieno[3,2-c] or [2,3-b]carbazoles and indolo[3,2-b]benzo[b]thiophenes. This constitutes a novel synthetic route to both tetracyclic systems.

Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells.

DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.

Antifungal activity of synthetic di(hetero)arylamines based on the benzo[b]thiophene moiety

The antifungal activity of several di(hetero)arylamine derivatives of the benzo[b]thiophene system was evaluated against clinically relevant Candida, Aspergillus, and dermatophyte species by a broth macrodilution test based on CLSI (formerly NCCLS) guidelines. The most active compound showed a broad spectrum of activity (against all tested fungal strains, including fluconazole-resistant fungi), with particularly low MICs for dermatophytes. Results from the inhibition of the dimorphic transition in Candida albicans and flow cytometry studies further confirmed their biological activity. With this study it was possible to establish some structure-activity relationships (SARs). The hydroxy groups proved to be essential for the activity in the aryl derivatives. Furthermore, the spectrum of activity in the pyridine derivatives was broadened by the absence of the ester group on position 2 of the benzo[b]thiophene system.

Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases

For many years, in vitro and in vivo studies have reported that organosulfur compounds (OSCs), naturally found in Allium vegetables, are able to suppress the proliferation of various tumor cells. In spite of recent advances, the specific molecular mechanisms involved in OSC activity are still unclear. Considering the antiproliferative effects observed in cancer cells, we postulated that OSCs might target the cell division cycle (Cdc) 25 phosphatases which are crucial enzymes of the cell cycle. Our findings suggest phosphatases Cdc25 as possible targets of naturally occuring polysulfides contributing to their anticancer properties. We report on the inhibitory activity of tetrasulfides occurring naturally in garlic and onion towards the human Cdc25 phosphatases. Diallyl- and dipropyltetrasulfides have emerged as interesting irreversible inhibitors of the Cdc25 isoforms A and C in vitro. Furthermore, growth of both sensitive (MCF-7) and resistant (Vcr-R) human breast carcinoma cells was significantly decreased by these tetrasulfides. The observed antiproliferative effect appeared to be associated with a G2-M cell cycle arrest.

An Improved Method for the Synthesis of Aminothiophenes - Precursors of Thieno[2,3-b]pyrrole.

Thiophenes 2 can easily be synthesized in two steps by using phenyl isothiocyanate and activated methylene compounds.

A combination of friedel-crafts and lawesson reactions to 5-substituted-2,2´-bithiophenes

Fundacao para a Ci~Encia e Tecnologia. ICCTI/French Embassy - Technical and Scientific~Cooperation Programme.

A novel pathway for the synthesis of a carboxylic acid-functionalised Ru(II) terpyridine complex

A new terpyridinyl ruthenium(II) complex functionalised with a carboxylic acid moiety was synthesised. This complex was prepared according to two different pathways. The first one successively involves protection of the carboxylic group on the ligand before formation of the complex followed by hydrolysis. The second one is a new route based on oxidation of a furan ring directly on the complex.