Enediyne compounds - new promises in anticancer therapy

Abstract

Enediyne compounds - new promises in anticancer therapyScientists of all kinds have long been intrigued by the nature, action and potential of natural toxins that possess exceptional antibacterial and anticancer activities. These compounds, named enediynes, are among the most effective chemotherapeutic agents known. Often compared with intelligent weapons, due to the unique structure and sophisticated mechanism by which they destroy double-helical DNA, enediyne antibiotics are nowadays the most promising leaders in the anticancer therapy. Apart from their diversity, enediyne compounds share some structural and functional similarities. One fragment of a structure is responsible for the recognition and transport, another part acts as molecular trigger while the third, reactive enediyne unit, undergoes Bergman cycloaromatization and causes DNA breakage. Members of the enediyne family are already in clinical use to treat various cancers, but more general use is limited by their complex structure, which makes them formidable targets for synthetic chemists. There are three main approaches in the design of new enediyne-related compounds: improvement of enediyne "warheads", increasing the selectivity and control of chemical or photo-induced activation. This paper gives an overview of naturally occurring enediynes, their mode of action and efforts undertaken to design artificial enediyne-related DNA cleaving agents.

Synthesis, X-ray structure and antiproliferative activity of 3-benzylthio-4-propargylselenoquinoline

“…The synthetic methods for their preparation are of interest especially with regard to the synthesis of biologically active enediyne antitumor antibiotics or similar model molecules (Grissom et al, 1996;Jones and Found, 2002;Nicolaou and Dai, 1991;Gredicak and Jeric, 2007).…”

A novel sulfonamide non-classical carbenoid: a mechanistic study for the synthesis of enediynes

“…14a-c The unique cooperativity between the lithium atom and sulfonamide group which essentially results in the displacement of a (relatively poor) leaving group at an sp 2 centre is brought about by a threefold combination of properties: (i) Li-sulfonamide coordination facillitating the initial 1,4-addition reaction giving a geometrically defined addition product as depicted in Scheme 7 (ii) the formation of a sulfonamide-Li coordination complex, favouring the equilibrium shown in Scheme 16 by stabilising the addition product and (iii) activation of the sulfonyl group to nucleophilic attack by intramolecular coordination in a Lewis-acid manner as outlined in Scheme 11. As an additional note, it has occurred to us that such a coordinating effect may explain why PPh(o-An) 2 proved to be a superior mediator compared to other phosphines in Radosevich's synthesis 18 of enediynes since an additional coordination effect is available to stabilise the initial 1,4-addition product (32, Fig. 2).…”

“…We here report a protocol where unsymmetrical enediynes can be prepared via simple 1,4-addition of lithium acetylides to alkynyl sulfonamides. At first we considered that the mechanistic pathway would be similar to that described by Satoh, involving a carbenoid intermediate which undergoes a [1,2] shift to yield a diyne product (Scheme 2). 15 However, other work which allows control of the carbon-carbon bond forming process.…”

Anticancer Antibiotics

“…Calicheamicin (Mylotarg) (12), an antibody-targeted agent, has been approved in treatment of acute myelogenous leukemia. Moreover, SMANCS is used to treat hepatocellular carcinoma in Japan (Grediak and Jeri 2007;Kingston and Newman 2008). In June 2010, FDA recommended that Mylotarg would not be available to new patients due to the safety issues arisen from a clinical trial.…”