Recent Progress in the Development of Anticancer Agents

Abstract

Cancer chemotherapy started with the discovery of the cytostatic effect of N-mustard and its derivatives more than five decades ago. This observation opened the way for the synthesis of various alkylating agents, antimetabolites and antimitotics expliciting antitumour activity against several human malignancies. The considerable toxicity of these drugs however, limited their application and only hormone-active products were relatively well tolerated. Besides, the majority of human malignant tumours proved to be chemoresistant. Consequently, there was still an urgent need for finding less toxic compounds possessing broader antitumour spectrum. Therefore, it became obvious that better understanding of the cellular metabolism - due to revolution in molecular biology - yielded new targets for cancer chemotherapeutic agents. Key enzymes active in signal transduction pathways could be blocked by new substances. Cell cycle control could be influenced by apoptosis inducers. Mitotic division could be inhibited by antitubulin agents. Multidrug resistance (MDR) could be modified by revertants. New concepts also emerged: a) chemoprevention, which is based on the principle, that since carcinogenesis is a genetically determined, progressive multistep process it can timely be reconverted into the direction of normal cellular metabolism by redifferentiating agents; b) antimetastatic therapy: originally performed postoperatively as an adjuvant therapy nowadays before surgical intervention, in order to block vascular dissemination of tumor cells (neoadjuvant therapy); c) antiangiogenic therapy: substances capable to hinder the vessel production essential for the development of metastasis; d) antitelomerase molecules inhibiting the immortal division capacity of DNA in malignant cells. All these new research approaches necessitate to review the existing drugs which are in clinical use or are investigational agents against human malignancies.

Regioselective combination of 1,3-dinucleophiles such as 2-mercaptobenzimidazole, 5-mercapto-3-phenyltriazole and potassium thiocyanate with 2,2-dicyanooxiranes

“…To study the regioselectivity of 1,3-dinucleophiles such as 1H-1,3-benzimidazol-2-thiol and 5-phenyl-4H-1,2,4-triazol-3-thiol with 2,2-dicyanooxiranes, we have investigated the nucleophilic reaction of 1H-1,3-benzimidazol-2-thiol 2 with 2,2-dicyanooxiranes 1a-d to prepare of 2-arylidene [1,3]thiazolo[3,2,a]benzimidazol-3(2H)-one (3a-d) derivatives in mild reaction conditions in good to excellent yields (Scheme 1).…”

“…In these protocols (Scheme 1 and 2) we have investigated reactions of 2,2-dicyanooxiranes 1, which have three electron-deficient centers, with 1,3-dinucleophile such as 1H-1,3-benzimidazol-2-thiol 2 and 5-phenyl-4H-1,2,4-triazol-3-thiol 4 which afforded 2-arylidene [1,3] [1,2,4]triazol-6-one 5a-b derivatives, respectively. In these reactions 1,3-dinucleophiles act via regioselective on C β and C α of 2,2-dicyanooxiranes 1 which have three electron deficient centers.…”

“…1,2 Many synthetic small molecules from different groups of heterocycles with influence on carcinogenesis have been reported and several of them are currently in clinical trials. 3 Thiazolone nuclei fused to heterocyclic systems represent a very important class of compounds used mainly as intermediates for the preparation of bioactive compounds. For example, 2-arylidene- [1,3]thiazolo [3,2-a]benzimidazol-3(2H)-ones were found antibacterial agents, 4 inhibitors of ubiquitin ligase 5 and other enzymes, and they may be used for the treatment of viral and inflammatory diseases, neurological disorders and cancer.…”

“…3 Thiazolone nuclei fused to heterocyclic systems represent a very important class of compounds used mainly as intermediates for the preparation of bioactive compounds. For example, 2-arylidene- [1,3]thiazolo [3,2-a]benzimidazol-3(2H)-ones were found antibacterial agents, 4 inhibitors of ubiquitin ligase 5 and other enzymes, and they may be used for the treatment of viral and inflammatory diseases, neurological disorders and cancer. In addition, some isosteric thiazolo [3,4-a]benzimidazoles inhibit enteroviruses 6 and tumors.…”

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AbstractA group of heterocyclic compounds of condensed [1,3]thiazole with benzimidazole or triazole derivatives were obtained by the regioselective reactions of the 2,2-dicyanooxiranes with 1H-1,3-benzimidazol-2-thiol or 5-phenyl-4H-1,2,4-triazol-3-thiol respectively in good to excellent yields. Also, we performed a reaction between 2,2-oxiranedicarbonitrile reagents and potassium thiocyanate in acetic anhydride at room temperature and isolated 2-acetylimino-1,3-oxathiole derivatives.

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