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TANABE, C. A. Y. Study of miltefosine analogues synthesis aiming at new antineoplastic agents. 2011. 79f. Dissertacao (Mestrado) – Faculdade de ciencias Farmaceuticas, Universidade de Sao Paulo, Sao Paulo, 2011. Cancer is one of the major causes of death worldwide. Due to the lack of individual standard treatment for metastatic cancer, chemotherapy is still based in the use of significantly toxic drugs like anthracyclines and taxanes. Hence, there is a need to search for new anticancer agents. Alkylphospholipids recently emerged as a new antitumor class and its lead compound, miltefosine, has been used for the topical treatment of cutaneous metastasis in breast cancer. However, this drug exhibits gastrointestinal toxicity and hemolytic activity. We investigated miltefosine synthetic route as well as the synthesis of cycloalkyl analogues possibly less toxic and hemolytic. We started from miltefosine synthesis, which included four steps: a) generation of hexadecyl phosphorodichloridate; b) generation of 2-(hexadecyloxy)-3methyl-oxo-1,3,2-oxazaphospholane; c) generation of hexadecyl 2-(methylamino) ethyl phosphate; d) production of the final product miltefosine (hexadecylphosphocholine). The route was optimized, resulting in the desired drug. After that, several methods for symmetrical diols monoprotection were investigated aiming at the generation of ω-hydroxydecyl cycloalkylmethyl ethers to be further employed in miltefosine synthetic route aiming at alkoxycycloalkyl analogues. Several attempts were realized however unsuccessfully, preventing us to move on in these analogues synthesis. In a different approach, we started from cyclohexylethanol and, employing the synthetic route of miltefosine, obtained the third intermediate, 2-cyclohexylethyl 2(methylamino)ethyl phosphate pure. The methylation step, last one to obtain the cycloalkyl analogue, resulted in a dimethyl analogue instead of a trymethyl one. We believe that adjusting the reaction parameters, such as increasing reagents concentrations, should result in a successful methylation step. The intermediate obtained as well as the analogue planned might be future evaluated in terms of hemolytic potential and antitumor activity.

Estudo da síntese de análogos da miltefosina como potenciais agentes antineoplásicos