Synthesis of cryptolepine analogues as potential bioreducible anticancer agents

Scott Seville, Roger M. Phillips, Steven D. Shnyder, Colin W. Wright

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

A series of 10 novel nitro-analogues of cryptolepine (1) has been synthesised and these compounds were evaluated for their in-vitro cytotoxic properties as well as their potential for reductive activation by the cytosolic reductase enzymes NQO1 and NQO2. Molecular modelling studies suggest that cryptolepine is able to fit into the active site of NQO2 and thus raising the possibility that nitro-analogues of 1 could act as bioreductive prodrugs and be selectively reduced by NQO1 and NQO2 to more toxic species in cancer cells in which these enzymes are over-expressed. Analogues were screened against the RT112 cell line (high in NQO2), in the presence and absence of the essential cofactor dihydronicotinamide riboside (NRH), whereby all analogues were shown to be cytotoxic (IC50 < 2 μM) in the absence of NRH. With the addition of NRH, one analogue, 2-fluoro-7,9-dinitrocryptolepine (7), exhibited a 2.4-fold increase in cytotoxic activity. Several nitro-derivatives were also evaluated as substrates for purified human NQO1 and analogues that were found to be substrates were subsequently tested against the H460 (high NQO1) and BE (low NQO1) cell lines to detect in-vitro activation by NQO1. The analogue 8-chloro-9-nitrocryptolepine (9) was found to be the best substrate for NQO1 but it was not more toxic to H460 than to BE cells. Fluorescence laser confocal microscopy of 1 and several analogues showed that in contrast to 1 the analogues were not localised into the nucleus suggesting that their cytotoxic mode(s) of action are different. This study has identified novel substrates for both NQO1 and NQO2 and further work on nitrocryptolepine derivatives as a lead towards novel anticancer agents would be worthwhile.

Original languageEnglish
Pages (from-to)6353-6360
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number19
Early online date6 Jul 2007
DOIs
Publication statusPublished - 1 Oct 2007
Externally publishedYes

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Antineoplastic Agents
Poisons
Cells
Substrates
Confocal Microscopy
Chemical activation
Derivatives
Cell Line
Molecular modeling
Confocal microscopy
Prodrugs
Enzymes
Fluorescence Microscopy
Inhibitory Concentration 50
Catalytic Domain
Oxidoreductases
Fluorescence
cryptolepine
NRH - quinone oxidoreductase2
Lasers

Cite this

Seville, Scott ; Phillips, Roger M. ; Shnyder, Steven D. ; Wright, Colin W. / Synthesis of cryptolepine analogues as potential bioreducible anticancer agents. In: Bioorganic and Medicinal Chemistry. 2007 ; Vol. 15, No. 19. pp. 6353-6360.
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Synthesis of cryptolepine analogues as potential bioreducible anticancer agents. / Seville, Scott; Phillips, Roger M.; Shnyder, Steven D.; Wright, Colin W.

In: Bioorganic and Medicinal Chemistry, Vol. 15, No. 19, 01.10.2007, p. 6353-6360.

Research output: Contribution to journalArticle

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