Synthesis and biological evaluation of water-soluble derivatives of chiral gossypol as HIV fusion inhibitors targeting gp41

Yang, Jian; Li, Long-Long; Li, Ju-Rong; Yang, Jingxiang; Zhang, Fang; Chen, Gang; Yu, Rui; Ouyang, Wenjie; Wu, Shuwen

doi:10.1016/j.bmcl.2017.08.049

Cited by 14 publications

(4 citation statements)

References 14 publications

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“…Many therapeutic agents are marketed as a pure enantiomer to afford greater efficacy and/or to minimize toxicities (LaPlante et al, 2011b). The racemization of atropisomers due to limitation on bond rotation is time dependent with vastly different half-lives ranging from minutes to years depending on the extent of steric hindrance, electronic influences, temperature, solvents, and conditions (Yang et al, 2018). Many compounds may have rotational hindrance around a single bond, but these are generally very short lived and not detected.…”

Section: Discussionmentioning

confidence: 99%

“…Therapeutic agents that possess chiral axial centers are much less common than chiral compounds with a stereogenic center. Besides lesinurad, other drugs with a chiral axial center on the market are gossypol and telenzepine, as well as a drug under investigation by Bristol-Myers Squibb (BMS) (BMS-986142) (Eveleigh et al, 1989;Watterson et al, 2016;Yang et al, 2018). BMS-986142 is a reversible inhibitor of Bruton's tyrosine kinase, which is being evaluated in clinical trials for the treatment of autoimmune disorders such as lupus and rheumatoid arthritis.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Stereoselective Metabolism, Inhibitory Effect on Uric Acid Uptake Transporters, and Pharmacokinetics of Lesinurad Atropisomers

Yang¹,

Zhou²,

Shen³

et al. 2018

Drug Metab Dispos

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Lesinurad [Zurampic; 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)], a selective inhibitor of uric acid reabsorption transporters approved for the treatment of gout, is a racemate of two atropisomers. The objective of this investigation was to evaluate the stereoselectivity of metabolism, the inhibitory potency on kidney uric acid reabsorption transporters (URAT1 and OAT4), and the clinical pharmacokinetics of the lesinurad atropisomers. Incubations with human liver microsomes (HLM), recombinant CYP2C9, and recombinant CYP3A4 were carried out to characterize the stereoselective formation of three metabolites: M3 (hydroxylation), M4 (a dihydrodiol metabolite), and M6 (S-dealkylation). The formation of M3 in HLM with atropisomer 1 was approximately twice as much as that with atropisomer 2, whereas formation of M4 with atropisomer 1 was 8-to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among lesinurad and the atropisomers. Following oral administration of 400 mg lesinurad once daily for 14 days to healthy human volunteers, the systemic exposure (C max at steady state and area under the concentration-time curve from time zero to the time of dosing interval) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 stable cells expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of Stereoselective Metabolism, Inhibitory Effect on Uric Acid Uptake Transporters, and Pharmacokinetics of Lesinurad Atropisomers

Yang¹,

Zhou²,

Shen³

et al. 2018

Drug Metab Dispos

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“…It caused interest due to identification of new properties of its derivatives. A number of scientific studies demonstrated that, by molecular cross-links with polymeric carriers, gossypol loses its toxic properties while retaining antiviral and immunomodulating effects (19)(20)(21)(22). It is this approach upon which Kagocel development is based.…”

Section: Historymentioning

confidence: 99%

Preclinical and Clinical Evidence of Safety of Antiviral Drug with Immunomodulatory Activity

Borovskaya

2018

Serbian Journal of Experimental and Clinical Research

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Antiviral drug Kagocel is widely used in Russia for prevention and treatment of acute respiratory infection, influenza, and herpes. The drug belongs to the group of interferon inductors. The article contains the review and analytical evaluation of safety of antiviral drug Kagocel. Kagocel is registered in the Russian Federation and some CIS countries and refers to the group of interferon inducers. This is a chemical compound of carboxymethyl cellulose and low-molecular natural polyphenol gossypol common in cotton-plant (Gossypium spp.) which protects the plant from depredators and diseases. Authors pay a special attention to the analysis and generalization of data from preclinical and clinical studies including the control of related substances. Absence of free gossypol impurities guaranteed by highly sensitive and specific quality control methods. Preclinical studies data was analyzed and the results were presented with focus on reproductive safety of Kagocel® in immature and mature animals.. No negative effect on animals’ reproductive function was revealed including spermatogenesis and generative function. No long-term product effect on reproductive system or next generations of animals was recorded both at therapeutic doses and at doses 10 times their exceeding. The safety of the drug demonstrated on data obtained from numerous clinical trials, including those involving children aged 2 years and older. Th is confirms the safety of antiviral drug Kagocel usage in clinical practice, including pediatrics.

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“…There is an increasing interest in using gossypol as antivirus [32][33][34][35][36][37]. Gossypol has many other important effects, where both racemic mixture and enantiomers of gossypol inhibit replicating human immunodeficiency virus-type 1(HIV-1) [29,30]. The in vitro anti-amoebic effects of gossypol were reported against axenic trophozoites from five Entamoeba histolytica strains [31].…”

Section: Introductionmentioning

confidence: 99%

Silica Gel Chromatographic Methods for Identification, Isolation and Purification of Gossypol Acetic Acids Prepared in Lab

Amara,

Hesham El-Masry,

Salem

et al. 2024

Preprint

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Quite a number of cottonseed varieties are existed. The seeds of each variety produce a different amount of gossypol as a natural toxic compound. The increased interest in this natural product and its toxic effects were enhanced the demand for establishing simple silica-gel-based methods for its isolation, purification, and characterization. Historically, silica gel plays a significant role in isolation and purification of many different natural products. Silica gel is variants and can intro-duce a lab, simple tool for tracking a compound in certain plants during its purification process. In this study, gossypol was isolated and purified in the form of yellow crystals as gossypol acetic ac-id. Several methods and tools were used for its characterization including TLC, preparative TLC, silica gel column, UV/IR spectrophotometer and HPLC (Robust spherical silica gel). A compara-tive study between its amounts in both Egyptian and Chinese varieties were performed. Under the experimental condition, the Egyptian cottonseeds contain 8.705 gm/kg, while the Chinese contains 5.395 gm/kg. Thin Layer Chromatography (TLC) had been flourished the science of the phytochemistry and still popular till nowadays and is recommended for fast, accurate, and inex-pensive evaluation and quantification of gossypol. It is recommended to isolate and purify gossy-pol as gossypol acetic acid using optimized combined methods used in this study. Using Silica gel different protocols will assist and facilitate the parallel comparison and save the compact column from any unexpected contaminants during the purification steps. During each step the silica gel itself could be simply removed by paper filtration.

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Synthesis and biological evaluation of water-soluble derivatives of chiral gossypol as HIV fusion inhibitors targeting gp41

Cited by 14 publications

References 14 publications

Characterization of Stereoselective Metabolism, Inhibitory Effect on Uric Acid Uptake Transporters, and Pharmacokinetics of Lesinurad Atropisomers

Characterization of Stereoselective Metabolism, Inhibitory Effect on Uric Acid Uptake Transporters, and Pharmacokinetics of Lesinurad Atropisomers

Preclinical and Clinical Evidence of Safety of Antiviral Drug with Immunomodulatory Activity

Silica Gel Chromatographic Methods for Identification, Isolation and Purification of Gossypol Acetic Acids Prepared in Lab

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