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Abstract

Tumors consist of cells whose growth and morphological characteristics are markedly different from those of normal cells. Observation of human and animal models argue that tumor development proceeds via a process formally analogous to Darwinian evolution, in which a succession of genetic changes, each conferring one or another type of growth advantage, leads to the progressive conversion of normal human cells into cancer cells. During the past decade, research into the causes of human cancer has made significant progress. Despite that, cancer remains a major disease burden worldwide; therefore major efforts have to be done in order to improve our knowledge about the mechanisms of carcinogenesis and tumour development with the aim to find new therapies and to develop new anticancer drugs. The inhibition of key enzymes in the N-glycosilation pathway, such as Golgi α-mannosidase II, has shown clinical potential in cancer treatment. In our group the search for simple disaccharide mimetics containing dihydroxypyrrolidine moieties lead to the synthesis of potent and selective inhibitors of α-mannosidase. Starting from those results we focused on the search of new heterocyclic compounds having anti cancer activity. In this work is first presented the synthesis of a library of new dihydroxypyrrolidine-derivatives and of a library of new oxathiazinane dioxide-analogs with the aim to find new anti cancer compounds. Chiral pool synthesis, starting from D- and L- gulonic acid γ-lactone and from O-benzyl-D-serine, was applied. For each class of heterocyclic compounds considered, a large number of analogs was prepared, in order to approach a structure activity relationship. The compounds were evaluated for their inhibitory activity toward glycosidases and for their tumor cell growth inhibitory activity through MTS assays. We have found 3,4-dihydroxypyrrolidine derivatives that are not α-mannosidase inhibitors but that maintain a high cytotoxicity toward several cancer cell cultures.

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