Hydnocarpin

Structural Modification of Sylibin to Derivatives of Sylibin/Hydnocarpin D /Silandrin, and Evaluation of Their Cytotoxicity Against Cancer Cells.[Pubmed:34218782]

Curr Top Med Chem. 2021 Jul 1. pii: CTMC-EPUB-116410.

BACKGROUND: Flavonolignans like silybin, Hydnocarpin, and siliandrin are a group of natural compounds combining the structural moieties of flavonoid and phenylpropanoid (lignan). Hydnocarpin and silandrin were less explored because of trace occurrence in nature. OBJECTIVE: The present study aimed to develop a chemical conversion of silybin to Hydnocarpin, and siliandrin. Also, a series of amide derivatives would be synthesized and biologically evaluated with regard to their anti-cancer effects. METHODS: In order to selectively convert silybin to 23-iodo silybin, 23-iodo Hydnocarpin D and 23-iodo isosilandrin, the ratio of Ph3P, imidazole and molecular iodine was meticulously adjusted. These three iodide compounds were converted into amide compounds by chemical transformation. MTT method was applied to evaluate their anti-cancer potency. The binding affinity to related proteins was calculated by molecular docking. RESULTS: Totally, 45 new amido-derivatives were synthesized and structurally characterized by NMR and HRMS. Some of them showed moderate to good antiproliferative potency against cancer cells. The activity of compound 10j was further testified by colony formation assay and molecular docking. CONCLUSION: Synthesis of 23-iodo silybin, 23-iodo Hydnocarpin D and 23-iodo isosilandrin from silybin was successfully accomplished by one simple iodination reaction. Some of the amide derivatives of sylibin/Hydnocarpin D /silandrin exhibit a remarkable inhibitory effect of proliferation on cancer cells as compared to silybin. These results would pave the way for further investigation on the derivatives of flavonolignans for the treatment of cancer.

Inhibitory effect of hydnocarpin D on T-cell acute lymphoblastic leukemia via induction of autophagy-dependent ferroptosis.[Pubmed:33926261]

Exp Biol Med (Maywood). 2021 Jul;246(13):1541-1553.

Hydnocarpin D (HD) is a bioactive flavonolignan compound that possesses promising anti-tumor activity, although the mechanism is not fully understood. Using T cell acute lymphoblastic leukemia (T-ALL) cell lines Jurkat and Molt-4 as model system, we found that HD suppressed T-ALL proliferation in vitro, via induction of cell cycle arrest and subsequent apoptosis. Furthermore, HD increased the LC3-II levels and the formation of autophagolysosome vacuoles, both of which are markers for autophagy. The inhibition of autophagy by either knockdown of ATG5/7 or pre-treatment of 3-MA partially rescued HD-induced apoptosis, thus suggesting that autophagy enhanced the efficacy of HD. Interestingly, this cytotoxic autophagy triggered ferroptosis, as evidenced by the accumulation of lipid ROS and decrease of GSH and GPX4, while inhibition of autophagy impeded ferroptotic cell death. Our study suggests that HD triggers multiple cell death processes and is an interesting compound that should be evaluated in future preclinical studies.

Cytotoxic Stilbenes and Canthinone Alkaloids from Brucea antidysenterica (Simaroubaceae).[Pubmed:31816856]

Molecules. 2019 Dec 3;24(23). pii: molecules24234412.

A phytochemical study of the root and bark of Brucea antidysenterica J. F. Mill. (Simaroubaceae) afforded three new compounds, including a stilbene glycoside bruceanoside A (1), and two canthinone alkaloids bruceacanthinones A (3) and B (4), along with ten known secondary metabolites, rhaponticin (2), 1,11-dimethoxycanthin-6-one (5), canthin-6-one (6), 1-methoxycanthin-6-one (7), 2-methoxycanthin-6-one (8), 2-hydroxy-1,11-dimethoxycanthin-6-one (9), beta-carboline-1-propionic acid (10), cleomiscosin C (11), cleomiscosin A (12), and Hydnocarpin (13). The structures of all the compounds were determined using spectrometric and spectroscopic methods including 1D and 2D NMR, and HRSEIMS. The identities of the known compounds were further confirmed by comparison of their data with those reported in the literature. The root and bark methanolic extracts, the dichloromethane and ethyl acetate soluble fractions, and the isolated compounds (3-13), were assessed for their cytotoxicity against the cancer cell lines A-549, MCF-7, and PC-3. The results suggested that compounds in the extracts might possess a synergic action in their cytotoxicity.

Exploring Mitochondria-Mediated Intrinsic Apoptosis by New Phytochemical Entities: An Explicit Observation of Cytochrome c Dynamics on Lung and Melanoma Cancer Cells.[Pubmed:31393121]

J Med Chem. 2019 Sep 12;62(17):8311-8329.

Hydnocarpin (Hy) is a flavonoid isolated and purified from the seeds of Hydnocarpus wightiana Blume. Herein, we have developed a built-in semi-synthetic modification on Hy by one-pot multi-component reaction and a [3 + 2] cycloaddition strategy to append five membered isoxazole and isoxazolone as new phytochemical entities (NPCEs). Two selected NPCEs viz Hy-ISO-VIII and Hy-ISO-G from the library of 20 newly synthesized derivatives after in vitro screening unveiled promising cytotoxicity and induced caspase-mediated apoptosis against the human lung and melanoma cancer cells which were well supported by virtual screening based on ligand binding affinity and molecular dynamic simulations. As a new insight, we introduced surface-enhanced Raman spectroscopy to identify the chemo-marker molecular fingerprint to confirm the cellular uptake, cytochrome c release, and DNA fragmentation in a label-free manner. The present findings throw up a surfeit of seminal reasons behind the semi-synthetic modification of Hy, stepping forward to cancer chemotherapy.

[Lignans from seed of Hydnocarpus anthelminthica].[Pubmed:31090297]

Zhongguo Zhong Yao Za Zhi. 2019 Apr;44(7):1397-1402.

This project is to investigate lignans from the seed of Hydnocarpus anthelminthica. Thirteen lignans were isolated from the 95% ethanol extract of the seed of H. anthelminthica, by polyamide resin, Sephadex LH-20, ODS column chromatography and preparative HPLC. Their structures were elucidated as(+)-syringaresinol(1), lirioresinol A(2),(+)-medioresinol(3),(7R,8R,8'R)-4'-guaiacylglyceryl-evofolin B(4), leptolepisol C(5),(-)-(7R,7'R,7''R,8S,8'S,8''S)-4',4''-dihydroxy-3,3',3'',5,5',5''-hexamethoxy -7,9':7',9-diepoxy-4,8''-oxy-8,8'-sesquineolignan-7'',9''-diol(6),(-)-(7R,7'R,7'' R,8S,8'S,8''S)-4',4''-dihydroxy-3,3',3'',5,5'-pentamethoxy-7,9':7',9-diepoxy-4,8' '-oxy-8,8'ses-quineolignan-7'',9''-diol(7), ceplignan(8), hydnocarpusol(9), isoHydnocarpin(10),(-)-Hydnocarpin(11), Hydnocarpin(12), and Hydnocarpin-D(13) by spectroscopic data analysis. Compounds 1-8 were obtained from the genus Hydnocarpus for the first time.

[Chemical Constituents of Lonicerae Japonicae Flos].[Pubmed:30209907]

Zhong Yao Cai. 2016 Sep;39(9):2030-2.

Objective: To study the chemical constituents of the methylene chloride extract of Lonicerae Japonicae Flos. Methods: The compounds were isolated and purified by silica gel column chromatography,Sephadex LH-20 gel column chromatography and recrystallization. The structures were elucidated by the physical and chemical properties,MS,1H-NMR and13C-NMR spectroscopy. Results: Nine compounds were isolated and their structures were identified as beta-sitosterol( 1),benzoic acid( 2),5-hydroxy-7,3',4'-trimethoxyflavone( 3),tetrapedic acid B( 4),tricin( 5),Hydnocarpin D( 6),6,7,10-trihydroxy-8-octadecenoic acid( 7),5'-methoxyHydnocarpin-D( 8) and daucosterol( 9). Conclusion: Compound 2,4,7,8 are isolated from this plant,compounds 2,7,8 are isolated from Caprifoliaceae family for the first time.

Unconventional application of the Mitsunobu reaction: Selective flavonolignan dehydration yielding hydnocarpins.[Pubmed:27340458]

Beilstein J Org Chem. 2016 Apr 8;12:662-9.

Various Mitsunobu conditions were investigated for a series of flavonolignans (silybin A, silybin B, isosilybin A, and silychristin A) to achieve either selective esterification in position C-23 or dehydration in a one-pot reaction yielding the biologically important enantiomers of Hydnocarpin D, Hydnocarpin and isoHydnocarpin, respectively. This represents the only one-pot semi-synthetic method to access these flavonolignans in high yields.

"Non-Taxifolin" Derived Flavonolignans: Phytochemistry and Biology.[Pubmed:26429716]

Curr Pharm Des. 2015;21(38):5489-500.

Flavonolignans are plant natural products, composed of a flavonoid moiety and a lignan (phenylpropanoid) part. Current literature focuses on flavonolignans formed from taxifolin and coniferyl alcohol as e.g. silybin and its congeners from fruit extract from the purple variety of the milk thistle (Silybum marianum) denoted as "silymarin". This review describes chemistry and biological activity of so far neglected "non-taxifolin" based flavonolignans, derived from apigenin, luteolin, tricin, chrysoeriol, naringenin and eriodictyol, as the flavonoid part. Up-to-date knowledge on Hydnocarpin, Hydnocarpin-D, pseudotsuganol, hydnowightin, neoHydnocarpin, palstatin, salcolins A and B, anastatins A and B, sinaiticin, silyamandin and silandrin is summarized in the present paper. Most of non-taxifolin derived flavonolignans have been shown to exhibit in vitro and/or in vivo anti-hepatotoxic, anti-oxidant, free radical scavenging, anti-inflammatory, anti-proliferative, anti-cancer, chemotherapy potentiating, anti-melanogenic, anti-bacterial, vasorelaxing, anti-platelet aggregation and/or hypotriglyceridemic activity, often stronger than silybin. Many of these compounds inhibited Staphylococcus aureus multidrug resistance pump NorA and sensitized multidrug resistant cancer cell lines showing a potential as adjuvants. Non-taxifolin derived flavonolignans are a relatively unexplored group of compounds with interesting biological activity and great application potential. Their detailed study could provide a new insight into the biomimetic synthesis in order to obtain new compounds with greater activity and identify new lead structures for the biomedicinal research.

[Study on Chemical Constituents of Peanut Hull].[Pubmed:26415405]

Zhong Yao Cai. 2015 Feb;38(2):302-4.

OBJECTIVE: To investigate the chemical constituents of peanut hull. METHODS: Several chromatography methods such as silica gel and Sephadex LH-20 combined with recrystallization were applied to isolate the compounds. Based on spectrum technologies (MS,1H-NMR and 13C-NMR) and physico-chemical methods, structures of isolated compounds were identified. RESULTS: Twelve compounds were isolated and elucidated as luteolin (1), diosmetin (2), 5,7,3',4'-tetrahydroxy-8-prenyflavone (3),5,7,3'-trihydroxy-4'- methoxy-8-prenylflavone(4), eriodicrtyol (5), racemoflavone (6), Hydnocarpin (7), 5,7-dihydroxy chromone (8), 5-hydroxy-chromone- 7-O-beta-D-glucoside (9), ferulic acid (10), beta-sitosterol (11) and daucosterol(12). CONCLUSION: Except compounds 1, 5 and 8, all compounds are obtained from peanut hull for the first time.

Hydnocarpin-Type Flavonolignans: Semisynthesis and Inhibitory Effects on Staphylococcus aureus Biofilm Formation.[Pubmed:26273725]

J Nat Prod. 2015 Aug 28;78(8):2095-103.

A new, efficient, and general semisynthesis of Hydnocarpin-type flavonolignans was developed and optimized, enabling gram-scale production of Hydnocarpin D (2). Moreover, the syntheses of optically pure Hydnocarpin isomers [(10R,11R)-Hydnocarpin (1a), (10R,11R)-Hydnocarpin D (2a), and (10S,11S)-Hydnocarpin D (2b)], as well as the synthesis of isoHydnocarpin (8), were achieved for the first time utilizing this new method. The synthesis is based on the two-step transformation of the readily available flavonolignans from milk thistle (Silybum marianum), accessible by isolation from the commercial extract silymarin. The first step relies on the regioselective formylation of the C-3 hydroxy group of the dihydroflavonol-type precursor using the Vilsmeier-Haack reagent, followed by formic acid elimination by triethylamine in the second step. The synthesized compounds were effective inhibitors of Staphylococcus aureus biofilm formation, with (10S,11S)-Hydnocarpin D (2b) being the most potent inhibitor. Furthermore, the effect of glucose on biofilm formation was tested, and glucose decreased the biofilm inhibitory activity of 2b. Moreover, 2b increased the susceptibility of Staph. aureus to enrofloxacin.

An efficient in vitro and in vivo HPLC method for hydnocarpin in nanomicelles formulation.[Pubmed:26184450]

Biomed Chromatogr. 2016 Mar;30(3):432-9.

For quantitative and other related bioactive studies of Hydnocarpin, there is a need to establish an efficient, specific and sensitive analytical method (in vitro and in vivo). In this paper, an efficient HPLC method has been established and validated to analyze Hydnocarpin in a nanomicelle formulation for the first time. Various chromatographic conditions for in vitro and in vivo determinations were investigated, with the application examined by pharmacokinetics and tissue distribution studies. The analysis was carried out using an HPLC system with a Waters symmetry C18 column (4.6 x 150 mm, 5 microm) at 25 degrees C with a detecting wavelength of 342 nm. Eluting at a rate of 1.0 mL/min, a 65% methanol and 35% acetic acid solution (0.1%) served as the mobile phase for the in vitro determinations while a 62% methanol and 38% acetic acid solution (0.1%) was used for in vivo analysis with isoliquiritigenin as internal standard. The established in vitro linearity range for Hydnocarpin was 0.2-20 microg/mL (R(2) = 0.9996), with the biological (in vivo) samples following the same trend. The accuracy of the method was >99% (in vitro) and 92.4-105.3% (in vivo). Also, the precision met the acceptance criterion. These results indicate that the established method exhibited high specificity, accuracy, linearity and precision. Additionally, this efficient HPLC method was applied to pharmacokinetics and tissue distribution studies.

[Chemical constituents from a Tibetan medicine Meconopsis horridula].[Pubmed:25011245]

Zhongguo Zhong Yao Za Zhi. 2014 Apr;39(7):1152-6.

A phytochemical investigation on the aerial parts of a Tibetan medicine Meconopsis horridula, by solvent extraction, repeated chromatographies on silica gel, Sephadex LH-20, and preparative TLC techniques, led to the isolation of 9 compounds. By spectroscopic analysis and comparison of its 1H and 13C-NMR data with those in literatures, their structures were identified as oleracein E(1), N-( trans-p-coumaroyl) tyramine (2), chrysoeriol (3), apigenin (4), Hydnocarpin (5), p-coumaric acid glucosyl ester (6), stigmast-5-ene-3beta-ylformate (7), 3beta-hydroxy-7alpha-ethoxy-24beta-ethylcholest-5-ene (8), and beta-sitosterol (9), respectively, among which compounds 6-8 were isolated from the genus for the first time,and 1,3 were isolated from the species for the first time. A MTT method was applied to evaluate the cytotoxic activity of compounds 14 against the human hepatocellular liver carcinoma cell line (HepG2), and compound 1 showed significant cytotoxicity against HepG2,with its inhibitory rate of 52.2% at 10 micromol x L(-1).

Hydnocarpus: an ethnopharmacological, phytochemical and pharmacological review.[Pubmed:24732111]

J Ethnopharmacol. 2014 May 28;154(1):17-25.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Hydnocarpus (Flacourtiaceae) includes forty species that are spread across the globe. In the Indian System of Medicine, Hydnocarpus pentandrus (Buch.-Ham.) Oken. is primarily used for treating leprosy and other skin disorders. It is known as "Chaulmoogra" and is also used to treat other indications including constipation, inflammation, blood disorders, and worm infestations. Various species of Hydnocarpus are also used in traditional medicine in China, Thailand, Malaysia, and Myanmar for several skin disorders. To assess the therapeutic potential of species from the Hydnocarpus genus and to determine future avenues for research. METHODS: All relevant scientific literature published up to the end of December 2013 was retrieved via a library and electronic search (SciFinder, PubMed, ScienceDirect, and Google Scholar). Manual searches of traditional books like to ancient classics, including Vaidya Yoga Ratnavali, Siddha Materia Medica, and contemporary references including The Ayurvedic Pharmacopoeia of India and The Ayurveda Formulary, were also performed. RESULTS: Seed oil from species of the Hydnocarpus genus is used for medicinal purposes, predominantly for various skin disorders. This oil is reported to contain a characteristic class of compounds known as cyclopentenyl fatty acids. Furthermore, seeds of this genus are reported to contain triglycerides of fatty acids, sterols, flavonoids, and flavonolignans. Hydnocarpin, a flavonolignan, is reported to potentiate antimicrobial and anticancer activity. The extracts and compounds isolated from this plant show a wide spectrum of pharmacological properties, including antibacterial, antileprotic, antitubercular, antipsoriatic, antirheumatic, hypolipidemic, antidiabetic, anticancer, anti-inflammatory, and antioxidant activities. The antileprotic activity is postulated to be due to the cyclopentenyl fatty acids present in the seed oil. CONCLUSION: Flavonolignans have an interesting chemical motif, and Hydnocarpin and its congeners should be investigated for their activities and the mechanism underlying these activities. Multi-drug-resistant microbes are on the increase, and the possible inhibitory effect of these compounds when used with current antimicrobials should also be evaluated. Furthermore, unique cyclopentenyl fatty acids should also be investigated to understand the exact mechanism of action underlying antileprotic activity. Additional in depth phytochemical investigations of seed oil and extracts are required to tap the true potential of species from the Hydnocarpus genus.

[Study on chemical constituents of Callicarpa peii].[Pubmed:24134001]

Zhong Yao Cai. 2013 Apr;36(4):563-6.

OBJECTIVE: To study the chemical constituents of Callicarpa peii. METHODS: The chemical constituents were isolated and purified by chromatographic methods and elucidated by spectral analysis, including UV, IR, MS, 1H-NMR and 13C-NMR. RESULTS: Ten compounds were obtained and identified as oleanolic acid (1), 2beta, 3beta,19alpha-trihydroxy-12-en-28-ursolic acid (2), luteolin -7,4'-dimethylether (3), luteolin -3', 4', 7, -trimethylether (4), luteolin -4'-methylether (5), Hydnocarpin (6), luteolin (7), lyoniresinol 3alpha-O-beta-D-glucopyranoside (8), kelampayoside A (9), kaempferol -3-O-glucuronide (10). CONCLUSION: All these compounds are isolated from Callicarpa peii for the first time and compounds 3, 4, 6, 8 and 10 are isolated from this genus for the first time.