Synthesis of miltefosine analogs potentially antineoplastic and antitrypanosomal

• Grant number: 12/19279-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2012
• End date: November 30, 2013
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Carlota de Oliveira Rangel Yagui
• Grantee: João Pedro Nunes Gonçalves
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cancer can be considered an important problem of public health and became the second largest cause of death in the U.S.A. and responsible for about 13% of all deaths worldwide. Current antineoplastic chemotherapy is based mainly on drugs that have high toxicity, restricting their broad spectrum. Chaga's disease, caused by the protozoan Trypanosoma cruzi, similarly constitutes an important problem of public health and affects more than 10 million people around the world. Besides, the numbers of drugs available for the treatment of this disease are limited, which motivates the search for new molecules more effective and present less side effects. In this context, the group of alkylphosphocholines (APC) presents itself as a promising group of chemotherapeutic agents. Although the mechanism of action is not fully elucidated, it was proposed that APC can act in the cell membrane and inhibit the protein kinase C (PKC). Miltefosine or hexadecylphosphocholine, the prototype of APC's group, is already clinically approved for topical use in skin metastasis of breast cancer and for the treatment of visceral leishmaniasis. As T. cruzi and Leishmania spp. belong to the same family of protozoa, the Kinetoplastidae, the application of APC for Chaga´s disease has been investigated. However, miltefosine shows gastrointestinal toxicity and hemolytic action. In this project, we will study the synthesis of new analogs of alkylphosphocholines presenting a cycloalkane in the alkyl chain, as well as vary the alkyl chain extension, aiming at compounds presenting lower hemolytic potential as well as higher activity against tumors, trypanosome, and leishmania.(AU)