Structural requirements for biological activity among antileukemic glaucarubolone ester quassinoids

Kupchan, S. Morris; Lacadie, John A.; Howie, Gary A.; Sickles, Barry R.

doi:10.1021/jm00231a009

Cited by 38 publications

(19 citation statements)

References 6 publications

(15 reference statements)

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“…The wealth of information gathered in the last two decades has shown what structural features are required for the antineoplastic activity exhibited by the quassinoids (3). An A-ring enone function, a C 6 or a C15 ester function, and an oxymethylene bridge between C 8 and C11 or C13 are essential for optimal activity.…”

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confidence: 99%

Synthetic studies towards bruceantin. Part 1. Establishment of the carbon network

Darvesh¹,

Grant²,

MaGee³

et al. 1991

Can. J. Chem.

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SULTAN DARVESH, ANDREW S. GRANT, DAVID I. MAGEE, and ZDENEK VALENTA. Can. J. Chem. 69,712 (1991). In a synthetic approach to the biologically active quassinoid bruceantin 1, intermediate 47 was prepared, which contains all required C-atoms, rings A and B, and four of the 10 chiral centers of bruceantin. The possibilities for a convergent strategy were explored, in which a 5-carbon unit would be joined to a 15-carbon unit by three bonds. After the study of various alkylations and Michael additions needed for the key step, it was found that 3-iodo-1-trimethylsilyl-5-hexenyne 44 adds to the dianion of methyl ketone nitriles 3 and 13 chemo-, diastereo-, and enantioselectively.Key words: bruceantin, quassinoids, alkylation, Michael addition.SULTAN DARVESH, ANDREW S. GRANT, DAVID I. MAGEE et ZDENEK VALENTA. Can. J. Chem. 69,712 (1991) Dans une approche i la synthkse de la quassinoide bructantine (1) biologiquement active, on a prtpard I'intermtdiaire 47 qui contient tous les atomes de carbone requis, les cycles A et B ainsi que quatre des 10 centres chiraux de la bructantine. On a explort les possibilitks de strattgie convergente dans lesquelles une unit6 de cinq atomes de carbone serait relite i une unit6 de 15 atomes de carbone par trois liaisons. Aprts avoir ttudiC diverses alkylations et additions de Michael requises pour l'ttape clt, on a trouvt que le 3-iodo-I-trimtthylsilyl-hextn-5-yne (44) s'additionne aux dianions des mtthylcCtone-nitriles 3 et 13 d'une faqon chtmo-, diasttrdo-et tnantio-stlective.Mots clks : bructantine, quassinoides, alkylation, addition de Michael.[Traduit par la rtdaction]The last two decades have seen the Simaroubaceae family of the plant kingdom make a prominent mark in natural product chemistry. The bitter substances produced in plants of this family, known as the quassinoids (1, 2), have received increased attention with the finding that some of them possess strong antileukemic activity in the murine lymphocytic leukemia P-388 test system, in addition to antimalarial, amebicidal, and antiviral activities.The wealth of information gathered in the last two decades has shown what structural features are required for the antineoplastic activity exhibited by the quassinoids (3). An A-ring enone function, a C 6 or a C15 ester function, and an oxymethylene bridge between C 8 and C11 or C13 are essential for optimal activity. Due to this functional and stereochemical complexity, coupled with the potential use in cancer and other therapies, a considerable amount of synthetic activity has been expended towards these compounds (4). Four tetracyclic members of the C20 picrasane family have been synthesized, all in racemic form (5), and just recently an enantioselective synthesis has been reported for three others (4a). Finally, the synthesis of racemic 15-deoxybruceolide and a relay conversion of the naturally derived (-)-form of this compound into (-)-bruceantin 1 have been reported.(4/z). From the scarcity of completed syntheses, it is evident that much work is still required in this area, es...

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confidence: 99%

Synthetic studies towards bruceantin. Part 1. Establishment of the carbon network

Darvesh¹,

Grant²,

MaGee³

et al. 1991

Can. J. Chem.

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“…Previous reports on the cytotoxicity of neosergeolide (Silva et al, 2009) demonstrated that, as observed to other quassinoids (Kupchan et al, 1976;Lee et al, 1982;Lumonadio et al, 1991;Imamura et al, 1993;MataGreenwood et al, 2001;Jiang et al, 2008;Lau et al, 2009), it strongly inhibited the proliferation of tumor cells in spite of their histological origin. The present study was designed to evaluate the selectivity of neosergeolide to tumor cells in comparison to normal lymphocytes, and moreover, to elucidate the underlying mechanism of action.…”

Section: Discussionmentioning

confidence: 83%

Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: The role of mitochondrial permeability transition pore and DNA damage

Cavalcanti¹,

Costa²,

Carvalho³

et al. 2012

Pharmaceutical Biology

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“…Generation of Brca1 fp/fp p53 fp/fp Cre and p53 fp/fp Cre mice has been described previously 17,18. The mice were in a C57BL/6 and 129/Sv, mixed background.…”

Section: Methodsmentioning

confidence: 99%

Antitumor Agents. 282. 2′-(R)-O-Acetylglaucarubinone, a Quassinoid from Odyendyea gabonensis As a Potential Anti-Breast and Anti-Ovarian Cancer Agent

et al. 2010

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A new quassinoid, designated 2′-(R)-O-acetylglaucarubinone (1), and seven known quassinoids (2-8) were isolated, using bioactivity-guided separation, from the bark of Odyendyea gabonensis (Pierre) Engler [syn. Quassia gabonensis Pierre (Simaroubaceae)]. The structure of 1 was determined by spectroscopic analysis, and by semi-synthesis from glaucarubolone. Complete 1 H and 13 C NMR assignments of compounds 1-8 were also established from detailed analysis of twodimensional NMR spectra, and the reported configurations in odyendene (7) and odyendane (8) were corrected. Compound 1 showed potent cytotoxicity against multiple cancer cell lines. Further investigation using various types of breast and ovarian cancer cell lines suggested that 1 does not target the estrogen receptor (ER) or progesterone receptor (PR). When tested against mammary epithelial proliferation in vivo using a Brca1/p53-deficient mice model, 1 also caused significant reduction in mammary duct branching.* To whom correspondence should be addressed. . khlee@unc.edu. + Equal Contribution.Supporting Information Available. HPLC analysis of 1 (synthetic and natural), 2, and 4, and NMR spectra of compound 1. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Nat Prod. Author manuscript; available in PMC 2011 September 24. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptQuassinoids are known as the bitter principles of Simaroubacaeous plants.1 -3 They are highly oxygenated triterpenes and possess a wide spectrum of in vitro and in vivo biological activities, including antitumor, antimalarial, antiviral, anti-inflammatory, antifeedant, insecticidal, amoebicidal, anti-ulcer, and herbicidal.1 In particular, the quassinoid bruceantin was brought to a phase II clinical trial as an anticancer drug candidate;4 however, lack of significant efficacy in treating human cancer led to termination of its clinical development in the early 1980's.5 From the initial studies on various quassinoids, the mechanism of action was attributed to the inhibition of site-specific protein synthesis by prevention of ribosomal peptidyl transferase activity leading to termination of chain elongation.6 However, other postulated mechanisms for inhibition of cancer cell growth include, but are not limited to, inhibition of plasma membrane NADH oxidase activity,7 down-regulation of c-myc oncogene,8 and mitochondrial membrane depolarization with caspase-3 activation.9The stem bark of Odyendyea gabonensis (Pierre) Engler [syn. Quassia gabonensis Pierre (Simaroubacae)] is a source of quassinoids, and seven quassinoids, 2′-(S)-Oacetylglaucarubinone (2), glaucarubinone (3), ailanthinone (4), 2′-(R)-O-acetylglaucarubin (5), excelsin (6), odyendene (7), and odyendane (8), were previously isolated.10 -12 We have re-investigated the stem bark of this plant, due to its potent selective cytotoxicity against breast cancer cell lines in our prior studies aimed at discovering antitumor agents from high...

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Structural requirements for biological activity among antileukemic glaucarubolone ester quassinoids

Cited by 38 publications

References 6 publications

Synthetic studies towards bruceantin. Part 1. Establishment of the carbon network

Synthetic studies towards bruceantin. Part 1. Establishment of the carbon network

Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: The role of mitochondrial permeability transition pore and DNA damage

Antitumor Agents. 282. 2′-(R)-O-Acetylglaucarubinone, a Quassinoid from Odyendyea gabonensis As a Potential Anti-Breast and Anti-Ovarian Cancer Agent

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