.beta.-Lapachone: synthesis of derivatives and activities in tumor models

Abstract

In order to find a 3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione more potent than the naturally occurring 2,2-dimethyl derivative [beta-lapachone (10a)], we synthesized a series of analogous compounds with modifications at position 2 of the pyran ring or at positions 8 and 9 of the benzene ring. Of the compounds tested in vitro for inhibition of RNA-dependent DNA polymerase and in mice infected with Rauscher leukemia, all retained good enzyme activity. Inhibition of the reverse transcriptase activity of the 2,2-substituted derivatives 10b-e was as strong as 10a. However, only the 2-methyl-2-phenyl derivative 10e proved to be about as potent as the 2,2-dimethyl reference compound 10a in prolonging the mean survival time of mice with Rauscher leukemia virus induced leukemia.

β-Lapachone-induced reactive oxygen species (ROS) generation mediates autophagic cell death in glioma U87 MG cells

“…␤-Lapachone is a quinone-containing compound originally obtained from the lapacho tree in South America [5]. Previous studies found that ␤-lapachone, an effective chemotherapeutic and radio-sensitizing agent, selectively induces apoptosis in a number of human breast and prostate cancer cell lines that is dependent on expression level of NAD(P)H:quinine oxidoreductase 1 (NQO1) [6,7].…”

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

“…3,4-Dihydro-2,2-dimethyl-2H-naphthol [1,2-b]pyran-5,6-dione (␤-lapachone) is found in Pau d'arco trees (Tabebuia impetiginosa) and possesses antitumor activity against S-180 leukemic cells, Yoshida sarcoma cells, sarcoma 180 cells, and Walker 256 carcinoma cells in early studies (Docampo et al, 1979;Schaffner-Sabba et al, 1984;Chau et al, 1998). ARQ 501 is a fully synthetic ␤-lapachone and has been identified as a potent activator of E2F1.…”

Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication.

“…l3-Lapachone, which is isolated from plant extracts (9), has a variety of pharmacological effects (10,11). Toxicity data in humans are not available for (3-lapachone; it is well tolerated in mice at <40 mg/kg given i.v.…”

“…(unpublished data). The maximum tolerated dose is about 1250 mg/kg given orally in mouse and chicken (10). Curcumin, the major active component of the food flavor tumeric, has been eaten, up to 100 mg/day, for a thousand years, and pharmacological studies demonstrate its very low toxicity.…”