What are quassinoids and what are their potential medicinal uses?

Quassinoids: General Information

Quassinoids are highly oxygenated degraded triterpenoid compounds exclusively found in plants of the Simaroubaceae family, with demonstrated anti-cancer, anti-malarial, anti-inflammatory, and neuroprotective properties that make them promising candidates for modern therapeutic development. 1

Chemical Classification and Sources

• Quassinoids represent a class of degraded triterpene compounds with over 190 distinct structures identified between 2004 and 2018 2
• These compounds are extracted primarily from plants in the Simaroubaceae family, including Eurycoma longifolia, Picrasma quassioides, and Brucea species 1, 3
• The structural complexity includes highly oxygenated frameworks, with some variants classified as 18-nor-quassinoids representing unique structural modifications 4

Pharmacological Properties and Mechanisms

Anti-Cancer Activities

• Quassinoids demonstrate potent anti-proliferative effects against various tumor cell types, with standardized quassinoid compositions showing IC50 values as low as 5.97 μg/mL against LNCaP prostate cancer cells while maintaining significantly lower toxicity (IC50 59.26 μg/mL) toward normal prostate cells 5
• The anti-cancer mechanisms include suppression of protein synthesis, inhibition of HIF-1α and MYC signaling pathways, disruption of membrane polarization, and activation of apoptotic machinery 1
• Specific compounds induce G0/G1 phase cell cycle arrest through down-regulation of CDK4, CDK2, Cyclin D1, and Cyclin D3, with concurrent up-regulation of p21Waf1/Cip1 5
• At higher concentrations, quassinoids trigger G2M arrest leading to apoptotic cell death with detectable poly(ADP-ribose) polymerase cleavage 5
• In vivo xenograft models demonstrate significant tumor growth suppression at doses of 5-10 mg/kg via intraperitoneal injection 5

Hormone-Related Effects

• Quassinoids inhibit androgen receptor translocation to the nucleus, preventing transactivation of prostate-specific antigen (PSA) and resulting in significant reduction of PSA secretion 5
• This mechanism is particularly relevant for hormone-dependent cancers despite the traditional use of E. longifolia for testosterone enhancement 5

Anti-Malarial and Anti-Microbial Properties

• Multiple quassinoids exhibit anti-malarial activity, with computational studies showing binding energies ranging from -7.87 to -9.58 kcal/mol against dihydrofolate reductase (DHFR), superior to methotrexate's -7.80 kcal/mol 3
• Inhibition constants (Ki) for DHFR range from 0.095 to 1.71 μM, compared to methotrexate's 1.64 μM 3
• Compounds like 6-dehydrolongilactone and eurycomalide B show particular promise based on docking scores, drug-likeness, and ADMET properties 3

Neuroprotective Effects

• Quassinoids from Picrasma quassioides demonstrate neuroprotective activities against H2O2-induced oxidative damage in SH-SY5Y neuronal cells 4
• The neuroprotective mechanism involves suppression of cell apoptosis and downregulation of caspase-3 activation 4

Additional Therapeutic Properties

• Anti-inflammatory, anti-viral, anti-oxidative, and anti-diabetic effects have been documented across various quassinoid compounds 2
• The anti-leukemic activity of bruceantin, discovered in 1975, initially brought this compound class to scientific prominence 1

Clinical Development Considerations

• Over 150 quassinoids have been isolated and classified based on chemical structures and biological properties investigated in vitro and in vivo 1
• Future research focusing on chemical modifications is likely to generate more active and less toxic derivatives of natural quassinoids 1
• Representative compounds with established anti-cancer mechanisms include eurycomanone, bruceine D, dehydrobruceine B, and brusatol 2

Historical Context

• Quassinoids have been used for many years in folk medicine, particularly in South East Asia for treating sexual dysfunction, infertility, and various other ailments 1, 5
• The transition from traditional medicine to modern therapeutic applications represents a promising avenue for drug development targeting key prosurvival signaling pathways relevant for diverse pathologies 1