alpha-Lapachone

J Org Chem. 2015 Aug 7;80(15):7340-50.

Photoconversion of β-Lapachone to α-Lapachone via a Protonation-Assisted Singlet Excited State Pathway in Aqueous Solution: A Time-Resolved Spectroscopic Study.[Pubmed: 26133974 ]

METHODS AND RESULTS:
The photophysical and photochemical reactions of β-lapachone were studied using femtosecond transient absorption, nanosecond transient absorption, and nanosecond time-resolved resonance Raman spectroscopy techniques and density functional theory calculations. In acetonitrile, β-lapachone underwent an efficient intersystem crossing to form the triplet state of β-lapachone. However, in water-rich solutions, the singlet state of β-lapachone was predominantly quenched by the photoinduced protonation of the carbonyl group at the β position (O9). After protonation, a series of fast reaction steps occurred to eventually generate the triplet state α-lapachone intermediate. This triplet state of α-lapachone then underwent intersystem crossing to produce the ground singlet state of α-lapachone as the final product. 1,2-Naphthoquinone is examined in acetonitrile and water solutions in order to elucidate the important roles that water and the pyran ring play during the photoconversion from β-lapachone to α-lapachone. β-Lapachone can also be converted to α-lapachone in the ground state when a strong acid is added to an aqueous solution.
CONCLUSIONS:
Our investigation indicates that β-lapachone can be converted to α-lapachone by photoconversion in aqueous solutions by a protonation-assisted singlet excited state reaction or by an acid-assisted ground state reaction.

Invest New Drugs. 2010 Apr;28(2):139-44.

Comparison of the cytotoxic effect of lapachol, alpha-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells.[Pubmed: 19255723]

METHODS AND RESULTS:
The pentacyclic 1,4-naphthoquinones 1a-d were cytotoxic (IC(50) approximately 2-7 microM) to human leukemic cell lines K562 (oxidative stress-resistant), Lucena-1 (MDR phenotype) and Daudi. Fresh leukemic cells obtained from patients, some with the MDR phenotype, were also sensitive to these compounds. The pentacyclic 1,4-naphthoquinones 1a and 1c induced apoptotic cell death in cells from leukemic patients as determined by flow cytometry. Conversely, the cell lines were highly insensitive to lapachol (2) and alpha-Lapachone (3). Mitomycin-C inhibited cell proliferation at concentrations as low as 0.5 microM. The low toxicity against lymphocytes activated by phytohemagglutinin shows that these compounds are selective for the cancer cells studied.
CONCLUSIONS:
Previous data suggest that these compounds (1a-d) can be bioactivated in situ by reduction followed by rearrangement leading to enones, which are powerful alkylating agents. In contrast, lapachol (2) and beta-lapachone (3), which cannot be bioactivated by reduction, showed little activity against the same cell lines.

Parasitol Res. 2006 Sep;99(4):429-33.

Oxyrane derivative of alpha-lapachone is potent growth inhibitor of Trypanosoma cruzi epimastigote forms.[Pubmed: 16596415 ]

METHODS AND RESULTS:
The investigation of trypanocidal effects against Trypanosoma cruzi and cytotoxicity in VERO cell line of several oxyranes structurally related to beta-lapachone, nor-beta-lapachone, alpha-Lapachone, and 4-methoxy-1,2-naphthoquinone is described.
CONCLUSIONS:
It was found that the oxyranes 10 derived from alpha-Lapachone showed an approximately the same trypanocidal activity of beta-lapachone. In addition, all the oxyranes showed less cytotoxicity than the corresponding naphthoquinones.

Biochem Pharmacol. 2000 Nov 1;60(9):1367-79.

Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives-eleutherin, alpha lapachone, and beta lapachone.[Pubmed: 11008131]

Pyranonaphthoquinones have diverse biological activities against Gram-positive bacteria, fungi, and mycoplasms, and, recently, there has also been an increasing interest in their anti-cancer activity.
METHODS AND RESULTS:
This study includes three derivatives: eleutherin (compound 1), beta lapachone (compound 2), and its structural isomer, alpha-Lapachone (compound 3). The mechanism of topoisomerase II inhibition by the three derivatives was examined systematically with respect to the steps of the catalytic cycle of the enzyme. Etoposide, the prototypical enzyme poison, was used as a control and in combination with compounds 1-3 to localize their mechanism of action. The study revealed that eleutherin (1) and beta lapachone (2) inhibited topoisomerase II by inducing religation and dissociation of the enzyme from DNA in the presence of ATP. Whereas compound 2 was an "irreversible" inhibitor of topoisomerase II, compound 1 merely slowed the catalytic cycle of the enzyme. alpha Lapachone (3), on the other hand, inhibited initial non-covalent binding of topoisomerase II to DNA and, in addition, induced religation of DNA breaks (even in pre-established ternary complexes) before dissociating the enzyme from DNA.
CONCLUSIONS:
Compound 3 was an "irreversible" inhibitor of topoisomerase II. The diverse and unique mechanisms of topoisomerase II inhibition by pyranonaphthoquinone derivatives reveal novel ways to target the enzyme with potential for anti-cancer drug design.

Pharmazie. 2003 Oct;58(10):690-5.

Monoarylhydrazones of alpha-lapachone: synthesis, chemical properties and antineoplastic activity.[Pubmed: 14609278]

The biological activities of the naphthoquinones lapachol, extracted from trees of the genus Tabebuia and its cyclization products alpha and beta-lapachone, have been intensively studied.
METHODS AND RESULTS:
Giving continuity to the research about new derivatives obtained from the reaction of these naphthoquinones with amino-containing reagents, a series of arylhydrazones of alpha-Lapachone was synthesized and their antineoplastic activity was evaluated. This new structure is based on the great electrophilicity of 1,4-quinoidal carbonyl groups towards reagents containing nitrogen as nucleophilic centers, such as arylhydrazines.
CONCLUSIONS:
The products were assayed by the National Cancer Institute (NCI, USA) and their binding to DNA, redox properties and QSAR studies were also determined.