Gedunin

Gedunin, a naturally occurring Hsp90 inhibitor, is tetranortriterpenoid isolated from the Indian neem tree (Azadirachta indica).

Hsp90 (heat shock protein 90) is a chaperone protein stabilizes proteins against heat stress, and aids in protein degradation. Originally, this protein was isolated by extracting proteins from cells stressed by heating, dehydrating or by other means. It also stabilizes a number of proteins required for tumor growth, thereby Hsp90 inhibitors are investigated as anti-cancer drugs.

In vitro, Gedunin induces degradation of Hsp90-dependent client protein and displays anti-proliferative activity in SKBr3, CaCo-2 and MCF-7 cancer cell lines with IC50 of 3.22, 16.8 and 8.84 μM respectively1.

Gedunin treatment was shown to exhibit anti-malarial activity against P. falciparum in parasite development and [3H]-hypoxanthine uptake assays with IC50 values of 0.14 and 3.1 μM respectively 2. Using mouse model, gedunin was demonstrated to present remarkable anti-inflammatory and anti-nociceptive effects on zymosan-induced inflamed knee joints, modulation of different cell populations3.

References:
1.  Uddin SJ, Nahar L, Shilpi JA, et al. Gedunin, a limonoid from Xylocarpus granatum, inhibits the growth of CaCo-2 colon cancer cell line in vitro. Phytotherapy research : PTR. 2007;21(8):757-761.
2.  Lee SE, Kim MR, Kim JH, et al. Antimalarial activity of anthothecol derived from Khaya anthotheca (Meliaceae). Phytomedicine : international journal of phytotherapy and phytopharmacology. 2008;15(6-7):533-535.
3.  Conte FP, Ferraris FK, Costa TE, et al. Effect of gedunin on acute articular inflammation and hypernociception in mice. Molecules. 2015;20(2):2636-2657.

Gedunin inhibits pancreatic cancer by altering sonic hedgehog signaling pathway.[Pubmed:26988754]

Oncotarget. 2017 Feb 14;8(7):10891-10904.

INTRODUCTION: The lack of efficient treatment options for pancreatic cancer highlights the critical need for the development of novel and effective chemotherapeutic agents. The medicinal properties found in plants have been used to treat many different illnesses including cancers. This study focuses on the anticancer effects of Gedunin, a natural compound isolated from Azadirachta indica. METHODS: Anti-proliferative effect of Gedunin on pancreatic cancer cells was assessed using MTS assay. We used matrigel invasion assay, scratch assay, and soft agar colony formation assay to measure the anti-metastatic potential of Gedunin. Immunoblotting was performed to analyze the effect of Gedunin on the expression of key proteins involved in pancreatic cancer growth and metastasis. Gedunin induced apoptosis was measured using flow cytometric analysis. To further validate, xenograft studies with HPAC cells were performed. RESULTS: Gedunin treatment is highly effective in inducing death of pancreatic cancer cells via intrinsic and extrinsic mediated apoptosis. Our data further indicates that Gedunin inhibited metastasis of pancreatic cancer cells by decreasing their EMT, invasive, migratory and colony formation capabilities. Gedunin treatment also inhibited sonic hedgehog signaling pathways. Further, experiments with recombinant sonic hedgehog protein and Gli inhibitor (Gant-61) demonstrated that Gedunin induces its anti-metastatic effect through inhibition of sonic hedgehog signaling. The anti-cancer effect of Gedunin was further validated using xenograft mouse model. CONCLUSION: Overall, our data suggests that Gedunin could serve as a potent anticancer agent against pancreatic cancers.

Screening of process variables using Plackett-Burman design in the fabrication of gedunin-loaded liposomes.[Pubmed:27917681]

Artif Cells Nanomed Biotechnol. 2017 Aug;45(5):1011-1022.

This study is to screening the formulation and process variables that produce significant effect on the Gedunin-loaded liposome formulations by using quality-by-design approach. Placket-Burman screening design was used to screen the most influencing formulation and process variables. Mean vesicle size, zeta potential, entrapment efficiency, and loading capacity were found in the range of 112-990 nm, -19.39 to -39.20 mV, 45.25-87.60%, and 3.54-10.47%, respectively. Differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD) result suggested that Gedunin encapsulated within liposome as amorphous state. The analysis of Pareto chart represented that selected independent variables had a most significant effect on dependent variables.

Gaining Synthetic Appreciation for the Gedunin ABC Ring System.[Pubmed:28042894]

Chemistry. 2017 Feb 16;23(10):2282-2285.

Gedunin, first isolated in 1960, displays a remarkable range of biological activity, but has yet to receive dedicated synthetic attention from a ground up construction perspective. Presented herein is a successfully executed approach to the fully functionalized ABC ring system of this challengingly complex natural product.

Protective effect of gedunin on TLR-mediated inflammation by modulation of inflammasome activation and cytokine production: Evidence of a multitarget compound.[Pubmed:27641928]

Pharmacol Res. 2017 Jan;115:65-77.

Activation of toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) triggers an innate immune response, via cytokine production and inflammasome activation. Herein, we have investigated the modulatory effect of the natural limonoid Gedunin on TLR activation in vitro and in vivo. Intraperitoneal (i.p.) pre- and post-treatments of C57BL/6 mouse with Gedunin impaired the influx of mononuclear cells, eosinophils and neutrophils, as well as the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and nitric oxide (NO), triggered by lipopolysaccharide (LPS) in mouse pleura. Accordingly, in vitro post-treatment of immortalized murine macrophages with Gedunin also impaired LPS-induced production of such mediators. Gedunin diminished LPS-induced expression of the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) on pleural leukocytes in vivo and in immortalized macrophages in vitro. In line with this, Gedunin inhibited LPS-induced caspase-1 activation and the production of IL-1beta in vivo and in vitro. In addition, Gedunin treatment triggered the generation of the anti-inflammatory factors IL-10 and heme oxigenase-1 (HO-1) at resting conditions or upon stimulation. We also demonstrate that Gedunin effect is not restricted to TLR4-mediated response, since this compound diminished TNF-alpha, IL-6, NO, NLRP3 and IL-1beta, as well as enhanced IL-10 and HO-1, by macrophages stimulated with the TLR2 and TLR3 agonists, palmitoyl-3-Cys-Ser-(Lys)4 (PAM3) and polyriboinosinic:polyribocytidylic acid (POLY I:C), in vitro. In silico modeling studies revealed that Gedunin efficiently docked into caspase-1, TLR2, TLR3 and to the myeloid differentiation protein-2 (MD-2) component of TLR4. Overall, our data demonstrate that Gedunin modulates TLR4, TLR3 and TLR2-mediated responses and reveal new molecular targets for this compound.

Gedunin, a novel hsp90 inhibitor: semisynthesis of derivatives and preliminary structure-activity relationships.[Pubmed:18816111]

J Med Chem. 2008 Oct 23;51(20):6495-502.

Gedunin (1), a tetranortriterpenoid isolated from the Indian neem tree ( Azadirachta indica), was recently shown to manifest anticancer activity via inhibition of the 90 kDa heat shock protein (Hsp90) folding machinery and to induce the degradation of Hsp90-dependent client proteins similar to other Hsp90 inhibitors. The mechanism of action by which Gedunin induces client protein degradation remains undetermined, however, prior studies have demonstrated that it does not bind competitively versus ATP. In an effort to further probe the mechanism of action, 19 semisynthetic derivatives of Gedunin were prepared and their antiproliferative activity against MCF-7 and SkBr3 breast cancer cells determined. Although no compound was found to exhibit antiproliferative activity more effective than the natural product, functionalities critical for antiproliferative activity have been identified.

Antimalarial activity of anthothecol derived from Khaya anthotheca (Meliaceae).[Pubmed:17913482]

Phytomedicine. 2008 Jun;15(6-7):533-5.

Antimalarial activity of anthothecol, a limonoid of Khaya anthotheca (Meliaceae) against Plasmodium falciparum was tested using a [(3)H]-hypoxanthine and 48h culture assay in vitro. Anthotechol showed potent antimalarial activity against malaria parasites with IC(50) values of 1.4 and 0.17microM using two different assays. Also, Gedunin had antimalarial activity with IC(50) values of 3.1 and 0.14microM. However, the citrus limonoids, limonin and obacunone did not show any antimalarial activity. The antimalarial activities were compared with the three currently used antimalarial medicines quinine, chloroquinine and artemisinin.

Gedunin, a limonoid from Xylocarpus granatum, inhibits the growth of CaCo-2 colon cancer cell line in vitro.[Pubmed:17450509]

Phytother Res. 2007 Aug;21(8):757-61.

Xylocarpus granatum J. Konig (Meliaceae), commonly known as 'dhundul', is a Bangladeshi mangrove tree, and well distributed in a number of other countries of south-east Asia, Australia and east Africa. Traditionally, X. granatum has been used as an astringent and febrifuge, and also for the treatment of fever, malaria, thrush, cholera, dysentery and diarrhoea in many countries including Bangladesh. Two limonoids, Gedunin and 1alpha-hydroxy-1,2-dihydroGedunin, the latter being new, have been isolated from the bark of Xylocarpus granatum by reversed-phase preparative HPLC, and the structures were confirmed by spectroscopic means. The cytotoxic potential of Gedunin has been evaluated by the Promega's CellTiter 96 non-radioactive cell proliferation assay using the CaCo-2 colon cancer cell line (IC(50) = 16.83 microM). A summary of the biological activities of Gedunin reported to date is also presented.