Lapachol

Lapachol [84-79-7] M 226.3, m 140". Crystd from EtOH or diethyl ether. 

A two-step transformation of conjugated dienes into non-conjugated ones was proposed for the synthesis of the difficult to-obtain lapachol (355) (a member of a class of antimalarial agents having an activity against the Walker carcinosarcoma 256) from the more available isolapachol 352183. This method consists in an oxidative cyclization of isolapachol 352 by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to form a mixture of the products 353 and 354 (equation 127). Treatment of this mixture with dilute acid in... 

Methyl, 2-hydroxymethyl-, and 2-formylanthraquinones in the heart wood of teak (Tectona grandis, Verbenaceae) are effective in inhibiting termite activity (105). Several naphthoquinone derivatives including lapachol are thought to impart marine borer resistance to woods, e.q. that of Tabebuia quayacan (Bignoniaceae) (108). 

The Hooker oxidation, a classical and historic example of which is the conversion of lapachol 1... 

THE CHEMISTRY AND BIOLOGY OF LAPACHOL AND RELATED NATURAL PRODUCTS a AND (3-LAPACHONES... 

ABSTRACT This review describes a group of compounds related to the prenyl naphthoquinone lapachol. They exhibit interesting biological activities. Various aspects of the identification, biosynthesis, chemistry and biological properties are discussed. 

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]. 

Table 1 gives an up-to-date compilation of selected natural products in the lapachol, furan and pyran-naphthoquinones classes, together with their occurrence and the biological activities investigated for each. 

Table 1. Selected members of the natural naphthoquinones related to lapachol.

The naphthoquinones with acid hydroxyl function like lapachol are easily extracted with bases. They are also extracted in a Soxhlet apparatus with EtOH, and the resulting extract is then exhaustively extracted with AcOEt to yield a residue rich in naphthoquinones [115-116]. The naphthoquinones are mainly isolated from the wood and heartwood but there some examples of isolation from the roots [46, 48, 53, 58, 65, 66, 75, 78]. The study of commercial herbal products sold as Taheebo, Pau d Arco, Lapacho, and Ipe roxo carried out by Girard et al [117], showed important differences in the content of lapachol and other related naphthoquinones present in extracts of Tabebuia ssp Tabebuia rosea, T. cassinoides, T. impetiginosa, and T. chrisantha. Similar works using HPLC techniques have been carried out by Awang et al. [118]. 

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 preparation of the acetates (61) and (62) from lapachol was the first example of the formation of a chromenol by base-catalysed cyclisation of an allylquinone. The reaction proceeds by normal acetylation, apparently giving both isomers (63) and (64), followed by proton abstraction from the activated methylene group and rearrangement of the dienone system, Fig. (12) [139],... 

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]. 

A synthesis of lapachol using reaction conditions better than those used by Fieser was carried out by Fridman et al [149].They used the lithium salt of 2-hydroxy-1,4-naphthoquinone prepared in situ instead of the silver salt used for Fieser [150]. The lithium salt was prepared in situ by addition of lithium hydride to the frozen solution of the quinone in dimethyl sulfoxide, Fig. (14). As the solution thawed, the lithium quinone was slowly formed and was then alkylated with 3,3-dimethylallyl bromide. Lapachol was thus obtained in 40% yield. 

Fig.(14). Improved approach to synthesize lapachol from lawsone...

BIOLOGICAL ACTIVITY OF LAPACHOL, a-LAPACHONE, 0-LAPACHONE AND THEIR DERIVATIVES... 

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... 

Foumet and Munoz published a review on natural products as trypanocidal, antileishmanial and antimalarial drugs. Among the active natural products, they include some naphthoquinones related to lapachol [194]. 

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