Structure–activity relationships of quassinoids for eukaryotic protein synthesis

Fukamiya, Narihiko; Lee, Kuo Hsiung̀; Muhammad, Ilias; Murakami, Chika; Okano, Masayoshi; Harvey, Isabelle; Pelletier, Jerry

doi:10.1016/j.canlet.2004.04.023

Cited by 49 publications

(43 citation statements)

References 30 publications

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“…Quassinoids are a group of degraded triterpenes found in the family Simaroubaceae, that show many biological activities such as antitumor (Fukamiya et al 2005), antifeedant (Daido et al 1995), phytotoxic (De Feo et al 2003), antiviral (Apers et al 2002, and antihelmintic (Nunomura et al 2006). The antimalarial activity of some quassinoids like brusatol, glaucarubinone and quassin has been demonstrated previously (Wright 2005).…”

Section: Discussionmentioning

confidence: 99%

In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

Andrade‐Neto

Pohlit

Pinto

et al. 2007

Mem. Inst. Oswaldo Cruz

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In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae), the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae), respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae), all presented significant in vitro inhibition (more active than quinine and chloroquine) of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.Key words: neosergeolide -ellipticine -aspidocarpine -4-nerolidylcatechol -Pothomorphe peltata -Picrolemma spruceiAspidosperma spp.Malaria is the main cause of economic loss and high morbidity in the world today and continues to be endemic to tropical regions such as the Amazon. In the Brazilian Amazon, 1.6 million positive plates (thick smears) in a total of 8 million diagnostic tests for malaria were registered from January 2004 to February 2007 (Ministério da Saúde, Sivep-Malaria 2007). The lack of an effective vaccine and the increasing expansion of strains of Plasmodium falciparum presenting resistance towards commonly used, low-cost antimalarials make control of this disease difficult (Olliaro & Bloland 2001, Wellens & Plowe 2001, Vieira et al. 2001, Gonzales et al. 2003, Alecrim et al. 2006. As a result, the World Health Organization (WHO 1978(WHO , 1995 has been promoting research on natural product based drugs for treatment of disease and many plant species have been evaluated for antimalarial activity (Weniger et al. 2004). In these studies, emphasis has been on the discovery of lead compounds for drug development (Gundidza & Chinyanganya 1999). The rational search for active substances in medicinal plants is a very promising and cost-effective strategy for antimalarial drug discovery. This approach benefits from the accumulated knowledge of the curing capacity of plants possessed by inhabitants of malaria endemic regions and permits the extensive evaluation of natural products derived from these sources (Campbell et al. 1997, 1998, Brandão et al. 1992, 1997, Krettli et al. 2001, Andrade-Neto et al. 2004a.This triage of useful and effective plants is at the heart of traditional medicinal knowledge and is an extremely important source of therapeutic compounds in use today. Important semi-synthetic, low-cost, highly effective antimalarial drugs such as the quinolines (chloroquine, mefloquine, primaquine, etc.) and artemisinin derivatives (sodium artesunate, arteether, artemether, etc.) owe their initial discovery to the isolation and structural identi...

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Section: Discussionmentioning

confidence: 99%

In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

Andrade‐Neto

Pohlit

Pinto

et al. 2007

Mem. Inst. Oswaldo Cruz

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“…Quassinoids suppress tumor growth by inhibition of protein synthesis and the AP-1 transcription factor, induction of apoptosis, and down-regulation of the myc oncogene [20][21][22][23][24]. The quassinoid 6α-tigloyloxychapparrinone inhibits HIF-1α expression by reducing phosphorylation of eukaryotic translation initiation factor 4E [25].…”

Section: Introductionmentioning

confidence: 99%

Glaucarubinone inhibits colorectal cancer growth by suppression of hypoxia-inducible factor 1α and β-catenin via a p-21 activated kinase 1-dependent pathway

Huynh

Beutler

Shulkes

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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p-21-Activated kinase 1 (PAK1) enhances colorectal cancer (CRC) progression by stimulating Wnt/β-catenin, ERK and AKT pathways. PAK1 also promotes CRC survival via up-regulation of hypoxia-inducible factor 1α (HIF-1α), a key player in cancer survival. Glaucarubinone, a quassinoid natural product, inhibits pancreatic cancer growth by down-regulation of PAK1. The aim of this study was to investigate the effect of glaucarubinone on CRC growth and metastasis, and the mechanism involved. Cell proliferation was measured in vitro by [(3)H]-thymidine incorporation and in vivo by volume of tumor xenografts. Protein concentrations were measured by Western blotting of cell extracts. We report here that glaucarubinone inhibited CRC growth both in vitro and in vivo. The potency of glaucarubinone as an inhibitor of cell proliferation was negatively correlated to PAK1 expression in CRC cells. Glaucarubinone suppressed the expression of HIF-1α and β-catenin. Knockdown of PAK1 by shRNA enhanced inhibition by glaucarubinone while constitutively active PAK1 blocked the inhibitory effect. Our findings indicate that glaucarubinone inhibited CRC growth by down-regulation of HIF-1α and β-catenin via a PAK1-dependent pathway.

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“…Several constituents have been isolated from Simaroubaceae, mainly alkaloids with high cytotoxicity and quassinoids with antimalarial and cytotoxic characteristics (Nurhanan et al 2005). The antiplasmodial and cytotoxic properties of quassinoids are both linked to protein synthesis inhibition (Fukamiya et al 2005), and it is likely that parasite and host cell ribosomes are too similar to allow for the development of selective inhibitors (Wright 2005). Because some quassinoids have shown greater selectivity against P. falciparum than against cellular lines, chemical derivation has attracted much attention as supplying potential leads for drug design (Guo et al 2005).…”

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confidence: 99%

In vitro anti-microbial activity of the Cuban medicinal plants Simarouba glauca DC, Melaleuca leucadendron L and Artemisia absinthium L

Valdés

Martínez

Lizama

et al. 2008

Mem. Inst. Oswaldo Cruz

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Structure–activity relationships of quassinoids for eukaryotic protein synthesis

Cited by 49 publications

References 30 publications

In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

Glaucarubinone inhibits colorectal cancer growth by suppression of hypoxia-inducible factor 1α and β-catenin via a p-21 activated kinase 1-dependent pathway

In vitro anti-microbial activity of the Cuban medicinal plants Simarouba glauca DC, Melaleuca leucadendron L and Artemisia absinthium L

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