Study of the synthesis of benzyl alkyl ether analogs of miltefosine and erufosine.

Author(s)

Luciana de Moura Bueno

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2016-09-16

Examining board members

Carlota de Oliveira Rangel Yagui; Elizabeth Igne Ferreira; Daniela Gonçales Rando

• Advisor: Carlota de Oliveira Rangel Yagui

Abstract

Cancer corresponds to a group of diseases with increasing incidence over the years, and is currently considered a global problem. Traditional treatments mostly act on the genetic machinery causing cytotoxicity and debilitating patients. Therefore, the search for new drugs is of paramount importance to find more selective and less toxic drugs. The class of alkylphospholipids deserves attention for presenting several analogs with antitumor activity by acting on the cell membrane. This class has miltefosine as a structural prototype. Miltefosine exhibits potent antitumor activity in vitro and against some tumor models, and has been clinically approved for topical use in cutaneous metastases of breast cancer. However, this drug is associated with gastrointestinal toxicity and hemolytic activity. From this prototype, new analogs were synthesized resulting in erufosine, which besides antitumor activity is capable of stimulating the production of human bone marrow cells and can be administered intravenously, since it is less hemolytic. Other studies show that the presence of bulky groups in the nonpolar moiety of alkylphospholipids also reduces the hemolytic activity. In this work, we designed benzyl alkyl ether analogs of miltefosine and erufosine. We studied the synthesis of ω-hydroxibenzylalkyl ethers intermediates by means of a factorial design and studying the alkyl halide to be employed. Best reaction condition was defined as room temperature and reaction time of 6h, with yields of 38% and 43% for 10-(benzyloxy)decane-1-ol and 12-(benzyloxy)dodecane-1-ol, respectively. For the benzyl alkyl ether analogs, several reaction conditions were investigated by reacting the ω-hydroxibenzylalkyl ethers with phosphorus oxychloride and subsequently with N-methyl propanolamine (for erufosine analogs) or N-methyl ethanolamine (for miltefosine analog). In the sequence, N-methylation with methyl iodide was carried out for erufosine analogs. For mitefosine, the analog obtained was an N-methylphosphoethanolamine. Structures confirmation was based on NMR analysis. Owing to the complexity of the synthetic routes and mainly difficulty in purification of amphiphilic molecules, the analogs panned were not obtained in adequate quantities and degree of purity to be submitted to in vitro biological test. Nonetheless, this study already points to the possibility of the synthetic routes investigated to obtain the compounds designed, with need to improve final purification steps. (AU)

• FAPESP's process: 14/07811-7 - Synthesis and study of the hemolytic activity of alkyl benzyl ether analogs of erufosine
• Grantee: Luciana de Moura Bueno
• Support Opportunities: Scholarships in Brazil - Master