84 research outputs found
N-4 Alkyl Cytosine Derivatives Synthesis: A New Approach
The selective N-4 alkylation of cytosine plays a critical role in the synthesis of biologically active molecules. This work focuses on the development of practical reaction conditions toward a regioselective synthesis of N-4-alkyl cytosine derivatives. The sequence includes a direct and selective sulfonylation at the N-1 site of the cytosine, followed by the alkylation of the amino siteusing KHMDS in CH2Cl2/THF mixture, providing a fast and efficient approach consistent withpyrimidine-based drug design
Therapeutic potential of TRPM8 antagonists in prostate cancer.
Transient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer,
although its mechanism of action remains unclear. Here, we have characterized and investigated
the effects of TRPM8 modulators in prostate cancer aggressiveness disclosing the molecular
mechanism underlying their biological activity. Patch-clamp and calcium fluorometric assays were
used to characterize the synthesized compounds. Androgen-stimulated prostate cancer-derived
cells were challenged with the compounds and the DNA synthesis was investigated in a preliminary
screening. The most effective compounds were then employed to inhibit the pro-metastatic behavior
of in various PC-derived cells, at different degree of malignancy. The effect of the compounds
was then assayed in prostate cancer cell-derived 3D model and the molecular targets of selected
compounds were lastly identified using transcriptional and non-transcriptional reporter assays.
TRPM8 antagonists inhibit the androgen-dependent prostate cancer cell proliferation, migration
and invasiveness. They are highly effective in reverting the androgen-induced increase in prostate
cancer cell spheroid size. The compounds also revert the proliferation of castrate-resistant prostate
cancer cells, provided they express the androgen receptor. In contrast, no effects were recorded in
prostate cancer cells devoid of the receptor. Selected antagonists interfere in non-genomic androgen
action and abolish the androgen-induced androgen receptor/TRPM8 complex assembly as well as the
increase in intracellular calcium levels in prostate cancer cells. Our results shed light in the processes
controlling prostate cancer progression and make the transient receptor potential melastatin-8 as a
‘druggable’ target in the androgen receptor-expressing prostate cancers
Synthesis and cytotoxic activity evaluation of 2,3-thiazolidin-4-one derivatives on human breast cancer cell lines
It is well known that resveratrol (RSV) displayed cancer-preventing and anticancer properties but its clinical application is limited because of a low bioavailability and a rapid clearance from the circulation. Aim of this work was to synthesize pharmacologically active resveratrol analogs with an enhanced structural rigidity and bioavailability. In particular, we have synthesized a library of 2,3-thiazolidin-4-one derivatives in which a thiazolidinone nucleus connects two aromatic rings. Some of these compounds showed strong inhibitory effects on breast cancer cell growth. Our results indicate that some of thiazolidin-based resveratrol derivatives may become a new potent alternative tool for the treatment of human breast cancer
Cycloaddition reactions of thiazolidine derivatives. An approach to the synthesis of new functionalized heterocyclic systems
A one-pot procedure for the synthesis of two functionalized tricyclic systems having structures of benzo[g]isoquinoline-5,10-dione and dihydrothieno[2,3-b]naphto-4,9-dione (DTNQ) is described. These new series were synthesized from cycloaddition reactions between naphthoquinone and arylthiazolidine derivatives, the latter acting, respectively, as highly reactive N-aryl-idenedehydroalanine ethyl esters (2-AD) or as amino ester nucleophilic species. (C) 2001 Elsevier Science Ltd. All rights reserved
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