P-Lapachone

Because of such extensive application in folk medicine, it is easy to understand the interest that the lapachol, the related naphthoquinones a-lapachone, P-lapachone and other naphthoquinones derivatives, have aroused as potential drugs. In fact, a broad variety of biological activities have been described for this kind of compounds. Some examples are antitumor promoting activities [11-12], inactivators of human cytomegalovirus protease [13], antiprotozoal activity [14], trypanocidal activity [15], anticancer activity [16], and antibacterial and antifungal activities [17]. 

The work realized by Dauson et al [127] is of particular interest for the H NMR and 13C NMR assignments of these type of molecules. The isomers a-lapachone and P-lapachone can be easily distinguished, attending to the pattern that present the linear and angular pyranonaphthoquinones in their NMR spectra. In the H NMR spectra, the signals corresponding to the aromatic protons appear in two different forms. In the case of a-cycled compounds, the aromatic protons have a symmetric environment and the hydrogens H5 and Hg are equivalent as... 

Prof. Burton has recently prepared and characterized (by NMR) benzo[a] phenazines obtained by condensation of P-lapachone with 1,2-phenylenediamines [128]. 

Although it presents diverse stereogenic centers, the authors do not indicate if this compound was found as a racemic mixture. Dehydro-a-lapachone (58) and dehydro-p-lapachone (59) are formed by oxidative cyclisation of lapachol with DDQ [134-135]. The reduction of quinones to hydroquinones is a quick, quantitative, and reversible process, which is common both to ortho and para quinones [136]. The transformation of lapachol to p-lapachone in acid media was treated previously in section-2. 

The p-lapachone absorbing into the visible (X.max 424 nm in benzene) is cleanly and efficiently reduced to the corresponding semiquinone radical upon photolysis in degassed solutions, with alcohols, amines and P-amino... 

A new photochemical conditions with catalytic quantities of P-lapachone have been recently reported [140]. The P-lapachone acts as photosensitizer to promote selective C16-C21 bond cleavage of catharanthine (65) yielding 21a-cyano-16a-(methoxycarbonyl) cleavamine (66) quantitatively, Fig. (13). 

Complexes of lapachol with diverse metals like copper (II), iron (II), iron (III), chromium (III), aluminium (IE), yttrium (El), samarium (IE), gadolinium (IE), and dysprosium (IE) have been investigated [141-144]. Direct electrochemical synthesis of some metal derivatives of lapachol have been carried out [145]. Several P-lapachone hydrazo compounds were synthesized and characterized using spectroscopic techniques including X-ray analyses [146]. Selective aromatic reduction in pyranonaphthoquinones has also been reported [147-148]. 

Syntheses of a- and p- lapachones and their homologues were carried out by photochemical side chain introduction to quinone. Thus, 1,4-naphthoquinone photochemically reacted with 3-methyl-2-butenal to give 2-(3-methyl-2-butenoyl)-l,4-naphthalenediol (69), regiospecifically. The product (69) was successively treated with acid, with dichloroaluminiun hydride, and finally with iron (III) chloride to derive in turn to cromanon (70), dihydropyran (71), and P-lapachone (35). P-lapachone was easily transformed to a-lapachone (38) by treating with acid. Likewise, from... 

Two short syntheses of P-lapachone from readily available naphthols and 3-methylbut-2-enal via a mild phenyl-boronic acid mediated cyclization to 2//-chromenes have been reported. Catalytic hydrogenation of 2H-chromenes with H /Pd-C in ethyl acetate afforded the corresponding naturally occurring chromanes (72) and (73). Oxidation of the adequate chromane with an excess of cerium ammonium nitrate (CAN) furnished P-lapachone in 62% yield [153]. 

P-lapachones carrying various substituents in position 2 were also synthesized starting with lawsone (9) and the corresponding allyl bromide adequately substituted, followed of cyclization with concentrated H2SO4 [154]. 

Barnes et al have carried out the synthesis of P-lapachone in eight steps with an overall yield of 23% starting from a-naphthol. The yields from... 

It has been recently reported by Nair et al an efficient protocol for the synthesis of a, P-lapachones derivatives based on hetero Diels-Alder trapping of 3-methylene-1,2,4-[3//] naphthalenetrione [158]. 

Biological investigations over the last years have shown that many of the medicinal properties claimed for Lapacho, Taheebo, Pau D Arco or Ipe Roxo are attibuted to the active components lapachol, a-lapachone, P-lapachone and their derivatives. 

Some synthetic lapachol derivatives have also showed cytotoxic activity. Burton et al have prepared mono(arylimino) derivatives of P-lapachone. Some of these derivatives had good scores with net cell kills in preliminary in vivo testing hollow fiber assays against a standard panel of 12 human tumor cell lines [160].Twelve substituted 1,4-naphthoquinones were tested against the ascitic form of sarcoma 180 in Swiss mice. Statistical analysis showed that the most important molecular parameter determining their effectiveness in prolonging the life of mice bearing this tumor is their redox potentials [161]. Zalkow et al have synthesized a monoimine quinone, namely 2-methyl-(Z)-4-phenylimino)naphth[2,3-d]oxazol-9-one, which in in vitro tests showed a selective activity for some solid cancer tumors [162]. Enamine derivatives of lapachol were... 

JA13474>. A trypanocidal phenazine derived from p-lapachone was found to be active against Trypanosoma cruzi, the microorganism that causes Chagas disease, and its structure was determined in part by X-ray crystallography <02JMC2112>. 

Lapachol, an alcohol that can be converted into P-lapachone (21), a prenyl-naphto-l,2-quinone known for its anti-tumoral, pro-apoptopic and topoisomerase I-inhibitory properties was obtained from the lapacho tree, Tabebuia avellanadae (Bignoniaceae). Although an inhibition of PTKs has not, to our knowledge, been reported, P-lapachone inhibited the activation of INK and MEK by tumour necrosis factor (TNF). These effects may account for the observed inhibition of the NF-KB-mediated gene expression and the mentioned biological activity [71],... 

THE CHEMISTRY AND BIOLOGY OF LAPACHOL AND RELATED NATURAL PRODUCTS a AND P-LAPACHONES... 

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