Identification and development of new antitumor agents with multi-target action

My research work has been focused on the design, synthesis, and evaluation of new antitumor agents with particular attention to their potential multi-target activity. Tumor is a multifactorial disease characterised by inflammation and hypoxic environment and both these conditions lead to an altered extracellular pH that favour cancer invasion of adjacent tissues. Tumor cells modify their energy metabolic activity to have advantages for the tumorigenesis. A promising approach to obtain anticancer agents could be represented by the identification of new small molecules capable to inhibit more than one enzyme involved in in tumoral growth. Between these enzymes, Cyclooxygenase, Carbonic Anhydrase and Kinase are attractive from the poli-pharmacological point of view. Indeed, both the design of isozyme selective COX and CA inhibitors, and the design of dual Abl/c-Src Kinase inhibitors are promising approaches to the identification of new anti-cancer agents. Different libraries of coumarin and their psoralen analogues EMAC10155, EMAC10156, EMAC10157, EMAC10158, EMAC10159, EMAC10160, EMAC10161 and EMAC10162 have been designed and synthesised with the purpose to further explore the influences of structural modifications on the coumarin and the psoralen core on the activity and selectivity towards CA I, II, IX and XII. None of the new compounds exhibited activity towards the off-targets hCA I and II isozymes. Conversely, both coumarin and psoralen derivates were active against the tumour associated isoforms IX and XII. Different series of potential multi-target agents to investigate on the structural requisites for the selective inhibition of tumor overexpressed hCAs and COX-2 enzymes has been synthetized: EMA10190 and EMAC10191. They present a benzene-sulphonamide group, efficient for the inhibition of COX-2 enzyme, and capable to coordinate the hCAs zinc cofactor in the catalytic site. This essential moiety binds a differently substituted central heterocyclic core either through a hydrazine or a thiazole spacer. Substitutions of the phenyl ring bonded to the hydrazine spacer or to the thiazole spacer is determinant to the selectivity toward the CA tumoral isoform, in particular toward the isoform IX. During my stay at the Lead Discovery Siena, I have designed and synthetized new pyrazolo[3,4-d]pyrimidine compounds substituted in position N-1, C-4 and C-6 to investigate on their inhibition potential towards tyrosine kinase Src and for T315I mutant cells. Significantly, all of the compounds of this library were micromolar inhibitors of Abl and c-Src

Exploring new scaffolds for the dual inhibition of HIV-1 RT polymerase and ribonuclease associated functions

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. Pursuing on our investigation on potential anti HIV multi-target agents we have designed and synthesized a small library of biphenylhydrazo 4-arylthiazoles derivatives and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity. In particular, compound 2-{3- [(2-{4-[4-(hydroxynitroso)phenyl]-1,3-thiazol-2-yl} hydrazin-1-ylidene) methyl]-4-methoxyphenyl} benzamide bromide (EMAC2063) was the most potent towards RNaseH (IC50 = 4.5 mM)- and RDDP (IC50 = 8.0 mM) HIV RT-associated function

Investigating the Anticancer Activity of Isatin/Dihydropyrazole Hybrids

A series of isatin-dihydropyrazole hybrids have been synthesized in order to assess their potential as anticancer agents. In particular, 12 compounds were evaluated for their antiproliferative activity toward A549, IGR39, U87, MDA-MB-231, MCF-7, BT474, BxPC-3, SKOV-3, and H1299 cell lines, and human foreskin fibroblasts. Four compounds exhibited interesting antiproliferative activity and were further examined to determine their EC 50 values toward a panel of selected tumor cell lines. The best compounds were then investigated for their induced mechanism of cell death. Preliminary structure-activity relationship indicates that the presence of a substituent such as a chlorine atom or a methyl moiety in position 5 of the isatin nucleus is beneficial for the antitumor activity. EMAC4001 proved the most promising compound within the studied series with EC 50 values ranging from 0.01 to 0.38 μM

Tuning the Dual Inhibition of Carbonic Anhydrase and Cyclooxygenase by Dihydrothiazole Benzensulfonamides

A novel series of of 4-[(3-phenyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides (EMAC10111a g) was synthesized and assayed toward both human carbonic anhydrase isozymes I, II, IX, and XII and cyclooxygenase isoforms. The majority of these derivatives preferentially inhibit hCA isoforms II and XII and hCOX-2 isozyme, indicating that 2,3,4-trisubstituted 2,3-dihydrothiazoles are a promising scaffold for the inhibition of hCA isozymes and of hCOX-2 enzyme. The nature of the substituent at the dihydrothiazole ring position 4 influenced the activity and selectivity toward both enzyme families. EMAC10111g resulted as the best performing compound toward both enzyme families and exhibited preferential activity toward hCA XII and hCOX-2 isozymes