Synthesis and anti-HIV activities of phorbol derivatives

Abstract

In this study, 37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated, building upon our previous synthesis of 51 phorbol derivatives. 12-Para-electron-acceptor-trans-cinnamoyl-13-decanoyl phorbol derivatives stood out, demonstrating remarkable anti-HIV-1 activities and inhibitory effects on syncytia formation. These derivatives exhibited a higher safety index compared with the positive control drug. Among them, 12-(trans-4-fluorocinnamoyl)-13-decanoyl phorbol, designated as compound 3c, exhibited the most potent anti-HIV-1 activity (EC₅₀ 2.9 nmol·L⁻¹, CC₅₀/EC₅₀ 11 117.24) and significantly inhibited the formation of syncytium (EC₅₀ 7.0 nmol·L⁻¹, CC₅₀/EC₅₀ 4891.43). Moreover, compound 3c is hypothesized to act both as an HIV-1 entry inhibitor and as an HIV-1 reverse transcriptase inhibitor. Isothermal titration calorimetry and molecular docking studies indicated that compound 3c may also function as a natural activator of protein kinase C (PKC). Therefore, compound 3c emerges as a potential candidate for developing new anti-HIV drugs.

Keywords

Phorbol esters / Anti-HIV-1 activity / Syncytia formation / 12-(Trans-4-fluorocinnamoyl)-13-decanoyl phorbol / Safety index / HIV-1 entry inhibitor / HIV-1 reverse transcriptase inhibitor / PKC activator

References

[1] Song YH, Zhang HG, Wang YM, et al. Importin KPNA2 confers HIV-1 pre-integration complex nuclear import by interacting with the capsid protein[J]. Antivir Res, 2022, 200: 105289.

[2] Korinek M, Wagh VD, Lo IW, et al. Antiallergic phorbol ester from the seeds of Aquilaria malaccensis[J]. Int J Mol Sci, 2016, 17(3): 398.

[3] Zhang DD, Zhou B, Yu JH, et al. Cytotoxic tigliane-type diterpenoids from Croton tiglium[J]. Tetrahedron, 2015, 71(52): 9638-9644.

[4] Chen H, Zhang R, Luo RH, et al. Anti-HIV activities and mechanism of 12-O-tricosanoylphorbol-20-acetate, a novel phorbol ester from Ostodes katharinae[J]. Molecules, 2017, 22(9): 1498.

[5] Tostes JB, Carvalho A, Silva A, et al. Phorbol esters from the latex of Euphorbia umbellata: bioguided isolation of highly potent HIV-1 latency interupters in virus reservoir cells[J]. J Nat Prod, 2021, 84(5): 1666-1670.

[6] Wang HB, Wang XY, Liu LP, et al. Tigliane diterpenoids from the Euphorbiaceae and Thymelaeaceae Families[J]. Chem Rev, 2015, 115(9): 2975-3011.

[7] Lee HK, Kim HS, Pyo M, et al. Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL Fas^lpr mice[J]. Theranostics, 2020, 10(22): 10186-10199.

[8] Gulakowski RJ, McMahon JB, Buckheit RW, et al. Antireplicative and anticytopathic activities of prostratin, a non-tumor-promoting phorbol ester, against human immunodeficiency virus (HIV)[J]. Antivir Res, 1997, 33(2): 87-97.

[9] Matsuya Y, Yu Z, Yamamoto N, et al. Synthesis of new phorbol derivatives having ethereal side chain and evaluation of their anti-HIV activity[J]. Bioorg Med Chem, 2005, 13(14): 4383-4388.

[10] Mekkawy SE, Meselhy MR, Nakamura N, et al. Anti-HIV-1 phorbol esters from the seeds of Croton tiglium[J]. Phytochemistry, 2000, 53(4): 457-464.

[11] Asada Y, Sukemori A, Watanabe T, et al. Isolation, structure determination, and anti-HIV evaluation of tigliane-type diterpenes and biflavonoid from Stellera chamaejasme[J]. J Nat Prod, 2013, 76(5): 852-857.

[12] Evans BE, Rittle KE, Bock MG, et al. Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists[J]. J Med Chem, 1988, 31(12): 2235-2246.

[13] Ueda R, Suzuki T, Mino K, et al. Identification of cell-active lysine specific demethylase 1-selective inhibitors[J]. J Am Chem Soc, 2009, 131(48): 17536-17537.

[14] Li QR. Preparation and Biological Activity of Phorbol Derivatives[D]. Soochow University, 2018: 22-65.

[15] Li QR, Zhang XQ, Cui XJ, et al. Optimization of preparation process of phorbol and synthesis, characterization and cytotoxicity of its derivatives[J]. Nat Prod Res Dev, 2019, 31(6): 1091-1100.

[16] Silinsky EM, Searl TJ. Phorbol esters and neurotransmitter release: more than just protein kinase C[J]. Brit J Pharmacol, 2003, 138(7): 1191-1201.

[17] Boudreault PL, Mattler JK, Wender PA. Studies on the regio- and diastereo-selective epoxidation of daphnanes and tiglianes[J]. Tetrahedron Lett, 2015, 56(23): 3423-3427.

[18] Liu YY, Liu YP, Wang XP, et al. Bioactive daphnane diterpenes from Wikstroemia chuii with their potential anti-inflammatory effects and anti-HIV activities[J]. Bioorg Chem, 2020, 105: 104388.

[19] Wang RR, Gao YD, Ma CH, et al. Mangiferin, an anti-HIV agent targeting protease effective against resistant strains[J]. Molecules, 2011, 16(5): 4264-4277.

[20] Tian CJ, Li SF, Huang N, et al. Daphnane diterpenoids from Trigonostemon lii and inhibition activities against HIV-1[J]. Nat Prod Bioprospect, 2020, 10(1): 37-44.

[21] Kumar KS, Rao AL, Rao MVB, et al. Synthesis and hypoglycemic and anti-inflammatory activity screening of novel substituted 5-[morpholino(phenyl)methyl]-thiazolidine-2,4-diones and their molecular docking studies[J]. Turk J Pharm Sci, 2019, 16(4): 380-391.

[22] Fisher HF, Singh N. Calorimetric methods for interpreting protein-ligand interactions[J]. Methods Enzymol, 1995, 259: 194-221.

[23] Chayrov1 RL, Stylos EK, Chatziathanasiadou MV, et al. Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation[J]. Amino Acids, 2018, 50: 1131-1143.

Funding

National Natural Science Foundation of China(81202882)

National Natural Science Foundation of China(82060670)

Suzhou Science and Technology Planning Project in Jiangsu Province of China(SNG2021022)

Priority Academic Program Development of the Jiangsu Higher Education Institutes, China(PAPD)

Project of Innovative Research Team of Yunnan Province(202005AE160005)