Salvador, Alessia (2008) Investigation about the mechanism of action of new antiproliferative compounds. [Ph.D. thesis]
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My research activity deals with the evaluation of the mechanism of action of new compounds with potential anticancer action. I studied molecules that demonstrated their antiproliferative activity without or after UV-A irradiation (photochemotherapics).
EVALUATION OF NEW POTENTIAL ANTICANCER AGENTS:
Quinoxalines and structure-related quinoxalinones represent an important class of molecules with antiproliferative activity. A series of new isoindolo[2,1-a]quinoxalin-6-ones derivatives was synthesized in Palermo University (Dipartimento Farmaco-Chimico, Tossicologico and Biologico) and the mechanism of action of the most active compound, ISQ3 , was evaluated. In fact, ISQ3 showed a very interesting antineoplastic activity reaching nanomolar IC50 values in many human tumor cell lines.
Cell death mode was checked through flow cytometry, searching for such typical apoptotic features as the loss of plasmatic membrane asymmetry after the exposure of phospholipids. This translocation is needed for the recognition of apoptotic cells by macrophages. Potential modifications in cell cycle were examined after the treatment with ISQ3. Then, the involvement of mitochondria in cell death was studied searching signals of a possible mitochondrial dysfunction. We started from the compound characteristics to find potential cellular targets.
EVALUATION OF NEW POTENTIAL PHOTOCHEMOTHERAPIC AGENTS:
PUVA therapy combines the action of psoralens with UV-A radiation for the cure of dermatological diseases with a hyperproliferative/ autoimmune character, for instance psoriasis, vitiligo and mycosis fungoides. This treatment presents some long-term adverse effects, such as mutagenesis and increased onset of cutaneous tumors, as a consequence of the formation of cross-links with DNA. Thus, there is an enhanced research of new derivatives with the same potency but devoid of the capability to induce DNA cross-links. In particular, the photochemical and photobiological properties of new angelicin, or angular furocoumarin, analogues, in which both oxygens were substituted with other heteroatoms, were studied. In fact, the synthesis of thiopyrano[2,3-e]indol-2-ones (L series) and pyrrolo[3,4-h]quinolin-2-ones (BV series) was conducted in Palermo University because the incapability of inducing DNA cross-links for geometry problems was supposed. Thus, DNA binding and photodamage properties, antiproliferative and phototoxic activity, the mechanism of cell death were evaluated for the most active compounds.
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