RESUMO
Podophyllotoxin (1) has been known to possess anti-tumor activity and is still considered an important lead for research and development of antineoplastic agents. Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. These agents are also used in combination therapies with other drugs. Due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. These issues provide strong impetus to a search for analogues of 1 with simplified structures, which can be accessible via short synthetic sequences from simple starting materials. Even if such initial compounds might have diminished cytotoxic potencies compared with the parent cyclolignan, the ease of preparation of carefully designed libraries of analogues would lead to more informative SAR studies and expeditious structure optimization. In this regard, during the last two decades considerable efforts have been made to synthesize aza- analogs of podophyllotoxin, i. e. aza-podophyllotoxins, with hetero atoms at different positions of the podophyllotoxin skeleton, while keeping the basic podophyllotoxin structure. Recently, there have been significant efforts towards the convenient synthesis of aza-analogs of 1. The use of multicomponent reactions (MCRs) and the synergies of ultrasound and microwave irradiations have increased the synthetic speed and variety of azapodophyllotoxins which are and will be available to be tested against a diverse population of carcinomas and other diseases. It has been reported that several aza-podophyllotoxins retain a great fraction of the cytotoxicity associated with the parent lignan. This review focuses on the strategies towards synthesis of various aza-podophyllotoxin analogues and their biological activities.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Técnicas de Química Sintética/métodos , Podofilotoxina/síntese química , Podofilotoxina/farmacologia , Podophyllum/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Podofilotoxina/química , Podofilotoxina/uso terapêuticoRESUMO
Semiquinone membrane/buffer partition coefficients have been determined for 1,2-naphthosemiquinone (ONQ.-), 1,4-naphthosemiquinone (NQ.-) and two of its hydroxylated derivatives, 5,8-dihydroxy-1,4-naphthosemiquinone (NZQ.-) and 5-hydroxy-1,4-naphthosemiquinone (JQ.-) as a function of membrane charge in multilamellar vesicles of phosphatidylcholine (PC) and equimolar mixtures of this lipid and phosphatidic acid (PC:PA) and cetyltrimethylammonium bromide (PC:CTAB) at physiological pH with the exception of values corresponding to PC:PA mixtures which were obtained at pH 9. These coefficients follow the order PC:PA < PC < PC:CTAB in agreement with the negative charge of the semiquinones. The disproportionation equilibria of the naphthosemiquinone derivatives are shifted to the semiquinone in the presence of neutral and positive membranes, being more pronounced in the latter. However, very low partition coefficients as well as small shifts in the semiquinone disproportionation equilibrium were observed for ONQ.- as compared to the other semiquinones. No partition of 1,4-benzosemiquinone (BQ.-) into the lipid phase was detected for either charged or neutral lipid membranes. The presence of lipid membranes decreases the BQ.- equilibrium concentration in the presence of all the types of membranes considered here.