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Master's Dissertation
DOI
10.11606/D.9.2011.tde-13032013-161330
Document
Author
Full name
Camila Ayami Yamamoto Tanabe
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2011
Supervisor
Committee
Yagui, Carlota de Oliveira Rangel (President)
Emery, Flavio da Silva
Matsutani, Guilherme Costa
Title in Portuguese
Estudo da síntese de análogos da miltefosina como potenciais agentes antineoplásicos
Keywords in Portuguese
Alquilfosfocolinas
Miltefosina
Planejamento de fármacos
Quimioterápicos
Abstract in Portuguese
O câncer é umas das principais causas de morte no mundo. Com a falta de critério individual para o tratamento de câncer metastático, a quimioterapia ainda é realizada com fármacos de toxicidade significativa como antraciclinas e taxanos. Portanto, a busca por novos fármacos é de suma importância. Os alquilfosfolipídios constituem uma nova classe de fármacos antineoplásicos, tendo como protótipo a miltefosina, empregada para o tratamento tópico de metástases cutâneas de câncer de mama. No entanto, este fármaco apresenta toxicidade gastrointestinal e ação hemolítica. Neste trabalho, investigou-se a rota sintética da miltefosina, bem como a síntese de novos análogos cicloalquílicos possivelmente menos hemolíticos e menos tóxicos. Para a síntese da miltefosina, 4 etapas foram realizadas: a) obtenção do Dicloreto de fosforoexadecila; b) obtenção de 2-(hexadeciloxi)-3-metil-oxa-1,3,2- oxazofosfolano; c) obtenção do fosfato de 2-(metilamino) etil hexadecila; d) obtenção da miltefosina (hexadecilfosfocolina); sendo o fármaco obtido com sucesso. Em seguida, metodologias de monossubstituição em dióis simétricos foram investigadas para obtenção de ω-hidroxidecil-cicloalquilmetil éteres a serem empregados na rota da miltefosina visando análogos alcoxicicloalquilicos. Diversas tentativas foram empregadas sem sucesso, impedindo-nos de dar continuidade à síntese destes análogos. Partindo-se do reagente cicloexanoetanol e empregando-se a rota de síntese aprimorada da miltefosina, obtivemos o intermediário fosfato de 2-(metilamino)etil cicloexila puro. A última etapa, referente à metilação da amina, resultou em composto dimetilado ao invés do trimetilado esperado. Um ajuste dos parâmetros reacionais como, por exemplo, aumento da concentração dos reagentes de partida, deve resultar no composto planejado. Tanto o intermediário obtido quanto o análogo desejado poderão ser futuramente ensaiados quanto à atividade antitumoral e potencial hemolítico.
Title in English
Study of miltefosine analogues synthesis aiming at new antineoplastic agents
Keywords in English
Alkylphosphocholines
Chemotherapeutic agents
Drug design
Miltefosine
Abstract in English
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)-3-methyl-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.
 
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Publishing Date
2013-04-01
 
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