Design, synthesis and biological evaluation of tubulin binding agents as anticancer hybrid compounds

Proponente Romano Silvestri - Professore Ordinario
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Giuseppe La Regina Componenti strutturati del gruppo di ricerca
Marianna Bufano Dottorando/Assegnista/Specializzando componente non strutturato del gruppo di ricerca
Marianna Nalli Componenti strutturati del gruppo di ricerca
Componente Qualifica Struttura Categoria
Paolo Manganini D2 Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca

Molecular hybridization aims to combine two biologically active compounds to form a new bioactive entity. Hybrid compounds may show affinity and efficacy superior to the parent compounds, better pharmacokinetic and pharmacodynamic properties, improved therapeutic index and reduced risk of unwanted side effects. In this research project, we aim to develop merged hybrid tubulin binding agents that are designed by overlapping the pharmacophore moieties of two active drugs and by joining them to obtain a single multiligand entity. These compounds take advantage that being relatively smaller compared to the "true" hybrids can potentially fit better into the colchicine site. Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are frequently used in combination for cancer therapy. We aim to obtain dual targeting microtubule and Top2 merged hybrids to achieve anticancer effects. Our strategy is to merge the ARDAP, ARAP and ATI scaffolds with structural features required for the Top2 inhibition, using YCH337 as a reference compound. The new compounds are expected to elicit inhibition of cancer cells, including the MDR cells, to arrest the cells in mitosis and to induce apoptosis. These compounds should behave differently from the combination of a microtubule inhibitor and a Top2 inhibitor, particularly in inducing apoptosis. To our knowledge, microtubule and carbonic anhydrase merged inhibitors have never been reported so far. We aim to synthesize first in class new inhibitors by including the characteristic pharmacophoric feature of the human carbonic anhydrase inhibitors, the benzensuldonamide moiety, into the ARDAP, ARAP and ATI scaffolds. The agents have potential to be used in the treatment of cancer, as well as in other pathologies, such as retinal and cerebral edema, glaucoma, epilepsy, as well as in preventing acute mountain sickness.

LS7_4, LS4_6, PE5_17

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