be carried out to ensure the safety of gedunin and its derivatives, especially for
semisynthetic derivatives of gedunin, which involve inorganic components and
chemicals in the production. To entirely elucidate the molecular mechanism action
of gedunin, more in-depth and holistic studies have yet to be carried out.
Acknowledgements This work is financially supported by Monash Global Asia in the 21st
Century (GA21) research grant (GA-HW-19-L01, GA-HW-19-L06 and GA-HW-19-S02);
University grants from the University of Malaya (PG136-2016A and PG135-2016A), External
Industry Grants from Biotek Abadi Sdn Bhd (vote no. GBA-81811A) and Fundamental Research
Grant Scheme (FRGS/1/2019/WAB09/MUSM/02/1 and FRGS/1/2019/SKK08/MUSM/02/7).
Author Contributions The writing was performed by K-YK, Y-SO, LT-HT, P-NY, K-BT. The
manuscript was further critically reviewed and improved by W-SY, S-YT, K-YK, Y-SO, LT-HT,
L-EL, L-HL and B-HG. While B-HG, LT-HT, L-HL provided vital guidance and insight to the
work. The project was conceptualized by B-HG.
References
Akihisa T, Nishimoto Y, Ogihara E, Matsumoto M, Zhang J, Abe M (2017) Nitric oxide
production-inhibitory activity of limonoids from Azadirachta indica and Melia azedarach.
Chem Biodiv 14(6).https://doi.org/10.1002/cbdv.201600468
Akihisa T, Noto T, Takahashi A, Fujita Y, Banno N, Tokuda H, Koike K, Suzuki T, Yasukawa K,
Kimura Y (2009) Melanogenesis inhibitory, anti-inflammatory, and chemopreventive effects of
limonoids from the seeds of Azadirachta indicia A. Juss. (neem). J Oleo Sci 58(11):581–594.
https://doi.org/10.5650/jos.58.581
Alzohairy MA (2016) Therapeutics role of Azadirachta indica (Neem) and their active constituents
in diseases prevention and treatment. Evidence Complement Alter Med ECAM
2016:7382506–7382506. https://doi.org/10.1155/2016/7382506
Atanasov AG, Waltenberger B, Pferschy-Wenzig E-M, Linder T, Wawrosch C, Uhrin P,
Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V,
Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H (2015) Discovery and resupply of
pharmacologically active plant-derived natural products: a review. Biotechnol Adv 33
(8):1582–1614. https://doi.org/10.1016/j.biotechadv.2015.08.001
Azirwan G, Thillaiampalam S, Muncharee T, Yokoyama N, Igarashi I (2019) In vitro inhibitory
effect of gedunin on Babesia and Theileria parasites. J Protozool Res 23(1–2):1–6
Badam L, Deolankar RP, Kulkarni MM, Nagsampgi BA, Wagh UV (1987) In vitro antimalarial
activity of neem (Azadirachta indica A. Juss) leaf and seed extracts. Indian J Malariol 24
(2):111–117
Bickii J, Njifutie N, Foyere JA, Basco LK, Ringwald P (2000) In vitro antimalarial activity of
limonoids from Khaya grandifoliola C.D.C. (Meliaceae). J Ethnopharmacol 69(1):27–33.
https://doi.org/10.1016/s0378-8741(99)00117-8
Bodduluru LN, Kasala ER, Thota N, Barua CC, Sistla R (2014) Chemopreventive and therapeutic
effects of nimbolide in cancer: the underlying mechanisms. Toxicol In vitro Int J Publ
Assoc BIBRA 28(5):1026–1035. https://doi.org/10.1016/j.tiv.2014.04.011
Boopalan T, Chaudhary A, Murali S, Arumugam A, Lopez R, Nandy S, Gutierrez C, Parada J,
Agullo P, Lakshmanaswamy R (2013) Abstract 2264: anti-cancer effect of gedunin against
pancreatic cancer cell lines. Can Res 73(8 Supplement):2264–2264. https://doi.org/10.1158/
1538-7445.am2013-2264
Borges PV, Moret KH, Raghavendra NM, Maramaldo Costa TE, Monteiro AP, Carneiro AB,
Pacheco P, Temerozo JR, Bou-Habib DC, das Gracas Henriques M, Penido C (2017)
582
Y. S. Ong et al.
semisynthetic derivatives of gedunin, which involve inorganic components and
chemicals in the production. To entirely elucidate the molecular mechanism action
of gedunin, more in-depth and holistic studies have yet to be carried out.
Acknowledgements This work is financially supported by Monash Global Asia in the 21st
Century (GA21) research grant (GA-HW-19-L01, GA-HW-19-L06 and GA-HW-19-S02);
University grants from the University of Malaya (PG136-2016A and PG135-2016A), External
Industry Grants from Biotek Abadi Sdn Bhd (vote no. GBA-81811A) and Fundamental Research
Grant Scheme (FRGS/1/2019/WAB09/MUSM/02/1 and FRGS/1/2019/SKK08/MUSM/02/7).
Author Contributions The writing was performed by K-YK, Y-SO, LT-HT, P-NY, K-BT. The
manuscript was further critically reviewed and improved by W-SY, S-YT, K-YK, Y-SO, LT-HT,
L-EL, L-HL and B-HG. While B-HG, LT-HT, L-HL provided vital guidance and insight to the
work. The project was conceptualized by B-HG.
References
Akihisa T, Nishimoto Y, Ogihara E, Matsumoto M, Zhang J, Abe M (2017) Nitric oxide
production-inhibitory activity of limonoids from Azadirachta indica and Melia azedarach.
Chem Biodiv 14(6).https://doi.org/10.1002/cbdv.201600468
Akihisa T, Noto T, Takahashi A, Fujita Y, Banno N, Tokuda H, Koike K, Suzuki T, Yasukawa K,
Kimura Y (2009) Melanogenesis inhibitory, anti-inflammatory, and chemopreventive effects of
limonoids from the seeds of Azadirachta indicia A. Juss. (neem). J Oleo Sci 58(11):581–594.
https://doi.org/10.5650/jos.58.581
Alzohairy MA (2016) Therapeutics role of Azadirachta indica (Neem) and their active constituents
in diseases prevention and treatment. Evidence Complement Alter Med ECAM
2016:7382506–7382506. https://doi.org/10.1155/2016/7382506
Atanasov AG, Waltenberger B, Pferschy-Wenzig E-M, Linder T, Wawrosch C, Uhrin P,
Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V,
Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H (2015) Discovery and resupply of
pharmacologically active plant-derived natural products: a review. Biotechnol Adv 33
(8):1582–1614. https://doi.org/10.1016/j.biotechadv.2015.08.001
Azirwan G, Thillaiampalam S, Muncharee T, Yokoyama N, Igarashi I (2019) In vitro inhibitory
effect of gedunin on Babesia and Theileria parasites. J Protozool Res 23(1–2):1–6
Badam L, Deolankar RP, Kulkarni MM, Nagsampgi BA, Wagh UV (1987) In vitro antimalarial
activity of neem (Azadirachta indica A. Juss) leaf and seed extracts. Indian J Malariol 24
(2):111–117
Bickii J, Njifutie N, Foyere JA, Basco LK, Ringwald P (2000) In vitro antimalarial activity of
limonoids from Khaya grandifoliola C.D.C. (Meliaceae). J Ethnopharmacol 69(1):27–33.
https://doi.org/10.1016/s0378-8741(99)00117-8
Bodduluru LN, Kasala ER, Thota N, Barua CC, Sistla R (2014) Chemopreventive and therapeutic
effects of nimbolide in cancer: the underlying mechanisms. Toxicol In vitro Int J Publ
Assoc BIBRA 28(5):1026–1035. https://doi.org/10.1016/j.tiv.2014.04.011
Boopalan T, Chaudhary A, Murali S, Arumugam A, Lopez R, Nandy S, Gutierrez C, Parada J,
Agullo P, Lakshmanaswamy R (2013) Abstract 2264: anti-cancer effect of gedunin against
pancreatic cancer cell lines. Can Res 73(8 Supplement):2264–2264. https://doi.org/10.1158/
1538-7445.am2013-2264
Borges PV, Moret KH, Raghavendra NM, Maramaldo Costa TE, Monteiro AP, Carneiro AB,
Pacheco P, Temerozo JR, Bou-Habib DC, das Gracas Henriques M, Penido C (2017)
582
Y. S. Ong et al.