Cepharanoline

Traditional herbal compounds as candidates to inhibit the SARS-CoV-2 main protease: an in silico study.[Pubmed:36719113]

J Biomol Struct Dyn. 2023 Mar;41(5):1603-1616.

COVID-19, a disease caused by the SARS-CoV-2 virus, is responsible for a pandemic since March 2020 and it has no cure. Therefore, herein, different theoretical methods were used to obtain potential candidates from herbal compounds to inhibit the SARS-CoV-2 main protease (M(pro)). Initially, the 16 best-scored compounds were selected from a library containing 4066 ligands using virtual screening by molecular docking. Among them, six molecules (physalin B 5,6-epoxide (PHY), methyl amentoflavone (MAM), withaphysalin C (WPC), daphnoline or trilobamine (TRI), Cepharanoline (CEP) and tetrandrine (TET)) were selected based on Lipinski's rule and ADMET analysis as criteria. These compounds complexed with the M(pro) were submitted to triplicate 100 ns molecular dynamics simulations. RMSD, RMSF, and radius of gyration results show that the overall protein structure is preserved along the simulation time. The average DeltaG(binding) values, calculated by the MM/PBSA method, were -41.7, -55.8, -45.2, -38.7, -49.3, and -57.9 kcal/mol for the PHY-M(pro), MAM-M(pro), WPC-M(pro), CEP-M(pro), TRI-M(pro), and TET-M(pro) complexes, respectively. Pairwise decomposition analyses revealed that the binding pocket is formed by His41-Val42, Met165-Glu166-Leu167, Asp187, and Gln189. The PLS regression model generated by QSPR analysis indicated that non-polar and polar groups with the presence of hydrogen bond acceptors play an important role in the herbal compounds-M(pro) interactions. Overall, we found six potential candidates to inhibit the SARS-CoV-2 M(pro) and highlighted key residues from the binding pocket that can be used for future drug design. Communicated by Ramaswamy H. Sarma.

Antiplasmodial activity of three bisbenzylisoquinoline alkaloids from the tuber of Stephania rotunda.[Pubmed:20981617]

Nat Prod Res. 2010 Nov;24(18):1766-70.

Three bisbenzylisoquinoline alkaloids were isolated for the first time from Stephania rotunda tuber. Their structures were elucidated by spectroscopic methods and their antiplasmodial activity was investigated in vitro on chloroquine resistant Plasmodium falciparum strain W2. These alkaloids were identified as 2-norcepharanthine (1), Cepharanoline (2) and fangchinoline (3). In vitro, they displayed significant antiplasmodial activity with inhibitory concentration 50 values of 0.3, 0.2 and 0.3 microM.

Inhibition of Na(+),K(+)-ATPase by the extract of Stephania cephararantha HAYATA and bisbenzylisoquinoline alkaloid cycleanine, a major constituent.[Pubmed:12907236]

Biochem Pharmacol. 2003 Aug 1;66(3):379-85.

The Stephania cephararantha HAYATA extract, and its constituent bisbenzylisoquinoline alkaloids, such as cycleanine, cepharanthine, isotetrandrine, berbamine, homoaromoline, and Cepharanoline were studied for effects on Na(+),K(+)-ATPase activity. The S. cephararantha HAYATA extract inhibited Na(+),K(+)-ATPase activity with an apparent IC(50) value of 540 microg/mL. Cycleanine markedly inhibited Na(+),K(+)-ATPase activity with an IC(50) value of 6.2 x 10(-4)M. It slightly inhibited Mg(2+)-ATPase, H(+)-ATPase, and Ca(2+)-ATPase. No effects on alkaline and acid phosphatase activities were observed. The inhibition by isotetrandrine, homoaromoline, cepharanthine, and berbamine was less marked, and Cepharanoline showed no effect. Five synthetic analogues of cepharanthine slightly inhibited the activity. The mechanism of inhibition by cycleanine on Na(+),K(+)-ATPase activity was examined in detail, and the following results were obtained in the overall reaction: (1) the mode of inhibition was noncompetitive with respect to ATP; (2) the degree of inhibition was decreased with a decrease of K(+) concentration; (3) it was not affected by Na(+) concentration; (4) the inhibition mechanism was different from that of ouabain. The activity of K(+)-dependent p-nitrophenyl phosphatase, a partial reaction of Na(+),K(+)-ATPase, did not appear to have been inhibited by cycleanine in the reaction mixture containing 15 mM K(+) (optimum condition). However, cycleanine increased the K(0.5) value for K(+) and reduced the K(i) values for Na(+) and ATP, in K(+)-dependent p-nitrophenyl phosphatase. Cycleanine might interact with the enzyme in Na.E(1)-P form and prevents the reaction step from Na.E(1)-P to E(2)-P.

Anti-HIV-1 activity and structure-activity relationship of cepharanoline derivatives in chronically infected cells.[Pubmed:11900350]

Antivir Chem Chemother. 2001 Sep;12(5):307-12.

Cepharanthine (12-O-methyl Cepharanoline) is a plant alkaloid and has been shown to inhibit tumour necrosis factor-alpha- or phorbol 12-myristate 13-acetate-induced HIV-1 replication in the chronically infected promonocytic cell line, U1. Its mechanism of action is considered to be the inhibition of nuclear factor kappaB, a potent inducer of HIV-1 gene expression. In this study, we have synthesized 96 derivatives of Cepharanoline, including cepharanthine, and examined their inhibitory effects on HIV-1 replication in U1 cells. Among the 12-O-alkyl derivatives, cepharanthine proved to be the most active, and the activity decreased as the length of the alkyl chain increased. All of the 12-O-acyl derivatives were totally inactive, while a few 12-O-carbamoyl derivatives displayed modest activity. Since 12-O-ethyl derivatives were found to be as active as cepharanthine against HIV-1 replication, we further synthesized various 12-O-ethyl derivatives of Cepharanoline. Among the derivatives, five proved to be more active inhibitors than cepharanthine, and the most active compound was 12-O-ethylpiperazinyl Cepharanoline. The 50% effective concentrations of this compound and cepharanthine were 0.0041 and 0.028 microg/ml (0.0060 and 0.046 microM), respectively.

Bisbenzylisoquinoline alkaloids from Stephania cepharantha and their effects on proliferation of cultured cells from the murine hair apparatus.[Pubmed:9342946]

Planta Med. 1997 Oct;63(5):425-8.

Bisbenzylisoquinoline alkaloids were isolated from Stephania cepharantha Hayata and their proliferative activities on cultured hair cells from the murine skin were evaluated. Cepharanthine (1), Cepharanoline (9), isotetrandrine (2), and berbamine (7) showed significant activities in the range of 0.01-0.1 microgram/ml, but had no activity on cultured keratinocytes or fibroblasts from the murine skin.

Histamine release inhibition activity of bisbenzylisoquinoline alkaloids.[Pubmed:1484888]

Planta Med. 1992 Dec;58(6):505-8.

Eleven examples of bisbenzylisoquinoline alkaloids (head-to-head; 10, head-to-tail; 1) and one half molecule type (N-methylcoclaurine), were tested by in vitro histamine release inhibition assay. The order of the potency of the inhibitory effect was ranked thus: homoaromoline, aromoline, isotetrandrine, cepharanthine, fangchinoline, obaberine, and tetrandrine. The following substances, Cepharanoline, berbamine, oxyacanthine, and cycleanine (head-to-tail structure) had no inhibitory effect. N-Methylcoclaurine showed an inhibitory effect comparable to that of fangchinoline.