Therapy6 | Main Goals

a) New therapeutic strategies for cancer drug discovery.

The plant-derived triterpenoids have a potencial interest as anticancer agents. New semisynthetic triterpenoid derivatives will be prepared in order to improve their antitumor activity. The cytotoxicity of these compounds will be evaluated against different types of cancer cells, such as prostate, breast, lung, colon, neuroblastoma, leukemia and pancreatic cancer. Cell cycle and apoptosis will be studied for the best compound of each series of triterpenoids. Further studies will be carried out to elucidate the cellular and molecular targets of the derivatives and determine their potential for drug discovery in cancer.

Developments on the antitumor activity of oxysterols and their sugar derivatives will be pursued. The main objective of this study is to shed light on the mechanisms of selective cytotoxicity for this class of natural products and derivatives.

Enzyme inhibitors act on hormone-dependent cancers, such as aromatase and sulfatase inhibitors on breast cancer and 5alpha-reductase and CYP17 inhibitors on prostatic cancer. Recent advances in drug discovery, using pharmacophore- and structure-based techniques will be used to perform molecular modelling studies for the rational design of promising lead compounds, which will be synthesised and biologically evaluated.

The PARP-1 mediated pathway is a major mechanism of DNA repair, accounting to drug resistance to DNA damaging anticancer agents. PARP-1 inhibition reverses anticancer chemoresistance and sensitizes cancer cells to chemotherapy. The recent PARP-1 structural data will provide accurate molecular modelling studies for new insights into PARP-1 structural features. Studies involving a structure based drug discovery will allow us to identify novel inhibitors acting in the known PARP-1 active site and also on alternative binding pockets, and to prepare them for further evaluation.

The understanding of the GPR30 receptor, concerning specific ligands, their structure and type of action, in vitro and in vivo, is another aim. Through SAR studies we will search for more effective ligands and will explore selective modifications on the estradiol scaffold and relative binding affinity of each compound to nuclear and membrane ERs. In vitro pharmacologic approaches and selective assays in cell lines differentially expressing those receptors will be done. From SAR studies, information about the receptor will be incorporated into a 3D model of GPR30 to direct future syntheses.

b) New therapeutic strategies for infectious diseases.

Microbial infections associated with inflammation disorders, are a huge problem of XXI century. Another goal will be to study antimicrobial resistance, the modulation of microbial factors on in vivo infection models and the pathophysiology of infections in order to unravel new therapeutic approaches and targets. Moreover, the group will pursue the biological evaluation of new molecules with antimicrobial and anti-inflammatory properties in new pathophysiological targets.

Multitarget therapies in malaria are a promising approach to circumvent drug resistance.
Oxysterols have been recently reported to increase the sensitivity of tumor cells to other chemotherapeutic agents. On the other hand, a library of oxysterols, synthesized in the group, has been evaluated for antiplasmodial activity against P. falciparum W2 and some of them presented low micromolar IC50 values. Knowing that drug resistance requires new drugs, the synthesis of hybrid antimalarials based on oxysterol scaffolds and stable tetraoxanes, synthetic analogues of artemisin, will be explored.

The collaboration with international highly qualified groups and the current training of students in these areas provides the ability to develop innovative research using the most robust tools in rational drug design to address relevant drug targets in cancer and infectious diseases.