Melanogenesis‐Inhibitory and Cytotoxic Activities of Chemical Constituents from the Leaves of Sauropus androgynus L. Merr. (Euphorbiaceae)

A new steroid, 20‐hydroxyisofucosterol (stigmasta‐5,24(28)‐diene‐3β,20β‐diol) ( 7 ), along with six known compounds 1 – 6 were isolated from the MeOH extract of the leaves of Sauropus androgynus L. Merr . (Euphorbiaceae). The structure of new steroid was determined by HR‐APCI‐MS and various NMR techniques in combination with literature data. Subsequently, their anti‐inflammatory, cytotoxic activities against five human cell lines, as well as inhibitory activities against the α‐MSH induced melanogenesis on the B16 cell line were evaluated. As the results, steroid compounds, 6 and 7 exhibited moderate cytotoxic to HL60, AZ521, SKBR3, and A549 tumor cell lines (IC₅₀ 26.9 – 45.1 μm ) with high tumor selectivity for A549 relative to WI38 cell lines (SI 2.6 and 3.0, resp.). And, flavonoid compounds, 4 and 5 exhibited superior inhibitory activities against melanogenesis (67.0 – 94.7% melanin content), even with no or low toxicity to the cells (90.1 – 99.6% cell viability) at the concentrations from 10 to 100 μm . Furthermore, Western blot analysis suggested that compound 5 could inhibit melanogenesis by suppressing the protein expressions of MITF, TRP‐1, TRP‐2, and tyrosinase.     

Biological Activities of Phenolics from the Fruits of Phyllanthus emblica L. (Euphorbiaceae)

Seven phenolic compounds, 1 – 7 , including a new organic acid gallate, mucic acid 1‐ethyl 6‐methyl ester 2‐O‐gallate ( 7 ), were isolated from the MeOH extract of the fruits of Phyllanthus emblica L. (Euphorbiaceae). The structures were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluated for their antioxidant abilities by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH), 2,2′‐azinobis(3‐ethylbenzthiazoline‐6‐sulfonic acid) (ABTS), and ferric reducing antioxidant power (FRAP) assays. The inhibitory activities against melanogenesis in B16 melanoma cells induced by α‐MSH, as well as cytotoxic activities against four human cancer cell lines were also evaluated. All phenolic compounds, 1 – 7 , exhibited potent antioxidant abilities (DPPH: IC₅₀ 5.6 – 12.9 μm ; ABTS: 0.87 – 8.43 μm Trolox/μm ; FRAP: 1.01 – 5.79 μm Fe²⁺/μm , respectively). Besides, 5 – 7 , also exhibited moderate inhibitory activities against melanogenesis (80.7 – 86.8% melanin content), even with no or low toxicity to the cells (93.5 – 101.6% cell viability) at a high concentration of 100 μm . Compounds 1 – 3 exhibited cytotoxic activity against one or more cell lines (IC₅₀ 13.9 – 68.4%), and compound 1 with high tumor selectivity for A549 (SI 3.2).     

Biological Activities of Triterpenoids and Phenolic Compounds from Myrica cerifera Bark

Seven triterpenoids, 1  –  7 , two diarylheptanoids, 8 and 9 , four phenolic compounds, 10  –  13 , and three other compounds, 14  –  16 , were isolated from the hexane and MeOH extracts of the bark of Myrica cerifera L. (Myricaceae). Among these compounds, betulin ( 1 ), ursolic acid ( 3 ), and myricanol ( 8 ) exhibited cytotoxic activities against HL60 (leukemia), A549 (lung), and SK‐BR‐3 (breast) human cancer cell lines (IC₅₀ 3.1 – 24.2 μm ). Compound 8 induced apoptotic cell death in HL60 cells (IC₅₀ 5.3 μm ) upon evaluation of the apoptosis‐inducing activity by flow cytometric analysis and by Hoechst 33342 staining method. Western blot analysis on HL60 cells revealed that 8 activated caspases‐3, ‐8, and ‐9 suggesting that 8 induced apoptosis via both mitochondrial and death receptor pathways in HL60. Upon evaluation of the melanogenesis‐inhibitory activity in B16 melanoma cells induced with α‐melanocyte‐stimulating hormone (α‐MSH), erythrodiol ( 7 ), 4‐hydroxy‐2‐methoxyphenyl β‐d ‐glucopyranoside ( 13 ), and butyl quinate ( 15 ) exhibited inhibitory effects (65.4 – 86.0% melanin content) with no, or almost no, toxicity to the cells (85.9 – 107.4% cell viability) at 100 μm concentration. In addition, 8 , myricanone ( 9 ), myricitrin ( 10 ), protocatechuic acid ( 11 ), and gallic acid ( 12 ) revealed potent DPPH radical‐scavenging activities (IC₅₀ 6.9 – 20.5 μm ).     

Synthesis of Novel Chiral Sulfonamide‐Bearing 1,2,4‐Triazole‐3‐thione Analogs Derived from D‐ and L‐Phenylalanine Esters as Potential Anti‐Influenza Agents

Novel enantiopure 1,2,4‐trizole‐3‐thiones containing a benzensulfonamide moiety were synthesized via multistep reaction sequence starting with D‐phenylalanine methyl ester and L‐phenylalanine ethyl ester as a source of chirality. The chemical structures of all compounds were characterized by elemental analysis, UV, IR, ¹H NMR, ¹³C NMR, 2D NMR (HETCOR), and mass spectral data. All compounds were tested in vitro antiviral activity against a broad variety of DNA and RNA viruses and in vitro cytostatic activity against murine leukemia (L1210), human T‐lymphocyte (CEM) and human cervix carcinoma (HeLa) cell lines. Although enantiopure 1,2,4‐triazole‐3‐thione analogs in (R) configuration emerged as promising anti‐influenza A H1N1 subtype in Madin Darby canine kidney cell cultures (MDCK), their enantiomers exhibited no activity. Especially compounds 18a , 21a , 22a , 23a , and 24a (EC₅₀: 6.5, 6.1, 2.4, 1.6, 1.7 μM, respectively) had excellent activity against influenza A H1N1 subtype compared to the reference drug ribavirin (EC₅₀: 8.0 μM). Several compounds have been found to inhibit proliferation of L1210, CEM and HeLa cell cultures with IC₅₀ in the 12–53 μM range. Compound 5a and 27a in (R) configuration were the most active compounds (IC₅₀: 12–22 μM for 5a and IC₅₀: 19–23 μM for 27a ). Chirality 28:495–513, 2016. © 2016 Wiley Periodicals, Inc.     

Superbanone,A New 2‐Aryl‐3‐benzofuranone and Other Bioactive Constituents from the Tube Roots of Butea superba

Phytochemical investigation from the tube roots of Butea superba, led to the isolation and identification of a new 2‐aryl‐3‐benzofuranone named superbanone ( 1 ), one benzoin, 2‐hydroxy‐1‐(2‐hydroxy‐4‐methoxyphenyl)‐2‐(4‐methoxyphenyl)ethanone ( 2 ), eight pterocarpans ( 3  –  10 ), and eleven isoflavonoids ( 11  –  21 ). Compound 2 was identified for the first time as a natural product. The structure of the isolated compounds was elucidated using spectroscopic methods, mainly 1D‐ and 2D‐NMR. The isolated compounds and their derivatives were evaluated for α‐glucosidase inhibitory and antimalarial activities. Compounds 3 , 7 , 8 , and 11 showed promising α‐glucosidase inhibitory activity (IC₅₀ = 13.71 ± 0.54, 23.54 ± 0.75, 28.83 ± 1.02, and 12.35 ± 0.36 μm , respectively). Compounds 3 and 11 were twofold less active than the standard drug acarbose (IC₅₀ = 6.54 ± 0.04 μm ). None of the tested compounds was found to be active against Plasmodium falciparum strain 94. On the basis of biological activity results, structure–activity relationships are discussed.     

Four New Tirucallane Triterpenoids from the Fruits of Melia azedarach and Their Cytotoxic Activities

Four new tirucallane triterpenoids, (21S,23R,24R)‐21,23‐epoxy‐21,24‐dihydroxy‐25‐methoxytirucall‐7‐en‐3‐one ( 2 ), (3S,21S,23R,24S)‐21,23‐epoxy‐21,25‐dimethoxytirucall‐7‐ene‐3,24‐diol ( 8 ), (21S,23R,24R)‐21,23‐epoxy‐24‐hydroxy‐21‐methoxytirucalla‐7,25‐dien‐3‐one ( 11 ), and (21S,23R,24R)‐21,23‐epoxy‐21,24‐dihydroxytirucalla‐7,25‐dien‐3‐one ( 12 ), along with 16 known analogues, 1 , 3  –  7 , 9  –  10 , and 13  –  20 , were isolated from the fruits of Melia azedarach. Their structures were elucidated by spectroscopic methods including 1D‐ and 2D‐NMR techniques and mass spectrometry. These compounds were evaluated for their cytotoxicities against HepG2 (liver), SGC7901 (stomach), K562 (leukemia), and HL60 (leukemia) cancer cell lines. Compound 20 exhibited potent cytotoxicity against HepG2 and SGC7901 cancer cells with the IC₅₀ values of 6.9 and 6.9 μm , respectively.     

Glycosidic Inhibitors of Melanogenesis from Leaves of Passiflora edulis

A new flavonoid glycoside, chrysin 6‐C‐β‐rutinoside (chrysin α‐L ‐rhamnopyranosyl‐(1→6)‐C‐β‐glucopyranoside; 2 ), and two new triterpene glycosides, (31R)‐31‐O‐methylpassiflorine ( 7 ) and (31S)‐31‐O‐methylpassiflorine ( 8 ), along with 14 known glycosides, including three flavonoid glycosides, 1, 3 , and 4 , six triterpene glycosides, 5, 6 , and 9 – 12 , three cyano glycosides, 13 – 15 , and two other glycosides, 16 and 17 , were isolated from a MeOH extract of the leaves of Passiflora edulis (passion flower; Passifloraceae). The structures of new compounds were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluation of compounds 1 – 17 against the melanogenesis in the B16 melanoma cells induced with α‐melanocyte‐stimulating hormone (α‐MSH), three compounds, isoorientin ( 1 ), 2 , and (6S,9R)‐roseoside ( 17 ), exhibited inhibitory effects with 37.3–47.2% reduction of melanin content with no, or almost no, toxicity to the cells (90.8–100.2% cell viability) at 100 μM . Western blot analysis showed that compound 2 reduced the protein levels of MITF, TRP‐1, and tyrosinase, in a concentration‐dependent manner while exerted almost no influence on the level of TRP‐2, suggesting that this compound inhibits melanogenesis on the α‐MSH‐stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of TRP‐1 and tyrosinase. In addition, compounds 1 – 17 were evaluated for their inhibitory effects against the Epstein? Barr virus early antigen (EBV‐EA) activation induced by 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in Raji cells.     

Phenolic Compounds from Clinopodium chinense (Benth.) O. Kuntze and Their Inhibitory Effects on α‐Glucosidase and Vascular Endothelial Cells Injury

Following an in vitro bioactivity‐guided fractionation procedure, 14 compounds including eight flavonoids and six phenylpropanoids were isolated and identified from the AcOEt fraction of Clinopodium chinense (Benth .) O. Kuntze . All constituents were tested for α‐glucosidase and high glucose‐induced injury in human umbilical vein endothelial cells (HUVECs) inhibitory activities. All constituents exhibited varying degrees α‐glucosidase inhibitory activity and protective activity on HUVECs. Among them, luteolin ( 2 ), eriodictyol ( 5 ), ethyl rosmarinate ( 13 ), and clinopodic acids B ( 14 ) were proved to be potent α‐glucosidase inhibitors with IC₅₀ value ranging from 0.6 to 2.0 μm . Additionally, luteolin ( 2 ), naringenin ( 4 ), eriodictyol ( 5 ), ethyl (2R)‐3‐(3, 4‐dihydroxyphenyl)‐2‐hydroxypropanate ( 9 ), caffeic acid ( 11 ), ethyl rosmarinate ( 13 ), and clinopodic acids B ( 14 ) significantly ameliorate HUVECs injury induced by high glucose with an approximate EC₅₀ value of 3 – 36 μm . These results suggest that the 14 bioactive constituents were responsible for hypoglycemic and protective vascular endothelium effect of C. chinense (Benth .) O. Kuntze and their structure–activity relationship was also analyzed briefly. Eriodictyol, luteolin, ethyl rosmarinate, and clinopodic acids B were the potential lead compounds of antidiabetic drugs.     

Chemical Components from Phaeanthus vietnamensis and Their Inhibitory NO Production in BV2 Cells

Phaeanthus vietnamensis Bân is a well‐known medicinal plant which has been used for the treatment of various inflammatory diseases in traditional medicine. Using various chromatographic methods, three new compounds, (7S,8R,8′R)‐9,9′‐epoxy‐3,5,3′,5′‐tetramethoxylignan‐4,4′,7‐triol ( 1 ), 8α‐hydroxyoplop‐11(12)‐en‐14‐one ( 5 ), and (1R,2S,4S)‐4‐acetyl‐2‐[(E)‐(cinnamoyloxy)]‐1‐methylcyclohexan‐1‐ol ( 12 ) along with twelve known compounds were isolated from the leaves of P. vietnamensis. Their chemical structures were elucidated by physical and chemical methods. All compounds were evaluated for the inhibitory activities of nitric oxide production in LPS‐stimulated BV2 cells. As the results, compound 6 showed the most potent inhibitory activity on LPS‐stimulated NO production in BV2 cells with the IC₅₀ values of 15.7 ± 1.2 μm . Compounds 2 , 7 , and 8 significantly inhibited inflammatory NO production with IC₅₀ values ranging from 22.6 to 25.3 μm .     

Two New Anti‐Proliferative C18‐Norditerpenes from the Roots of Podocarpus macrophyllus

Activity‐guided fractionation strategy was used to investigate chemical constituents from the roots of Podocarpus macrophyllus. Successfully, two new norditerpenes, 2β‐hydroxymakilactone A ( 1 ) and 3β‐hydroxymakilactone A ( 2 ), along with ten known analogues ( 3  –  12 ) were isolated. The structures of 1 and 2 were elucidated by spectroscopic analysis including 1D‐, 2D‐NMR, and HR‐ESI‐MS data. The previously reported structure of 2,3‐dihydro‐2α‐hydroxypodolide was revised as 2,3‐dihydro‐2β‐hydroxypodolide ( 3 ) by spectroscopic analysis, and was further confirmed by X‐ray crystallographic analysis. Cytotoxic activities of all isolated compounds against five human solid tumour cell lines (AGS, HeLa, MDA‐MB‐231, HepG‐2, and PANC‐1) were evaluated. All of them exhibited anti‐proliferative activities (IC₅₀ = 0.3 – 27 μm ), except for 10 . Compounds 1 , 4 , 5 , 6 , and 8 exhibited potent inhibitory activities with IC₅₀ < 1 μm against HeLa and AGS cells.     

Salvisertin A,a New Hexacyclic Triterpenoid,and Other Bioactive Terpenes from Salvia deserta Root

Using various chromatographic methods, a new hexacyclic triterpenoid, 2β,3β,24β‐trihydroxy‐12,13‐cyclotaraxer‐l4‐en‐28oic acid ( 1 ), together with ten known compounds, 2α,3α,23‐trihydroxyurs‐12,20(30)‐dien‐28oic acid ( 2 ), 6,7‐dehydroroyleanone ( 3 ), horminone ( 4 ), 7‐O‐methylhorminone ( 5 ), sugiol ( 6 ), demethylcryptojaponol ( 7 ), 14‐deoxycoleon U ( 8 ), 5,6‐didehydro‐7‐hydroxy‐taxodone ( 9 ), ferruginol ( 10 ), and dichroanone ( 11 ), were isolated from the roots of Salvia deserta. Their structures were identified on the basis of spectroscopic analysis and comparison with the reported data. The individual compounds ( 1 , 3  –  8 ) were screened for cytotoxic activity, using the sulforhodamine B bioassay (SRB) method. As the results, Compounds 3 , 5 , and 8 showed cytotoxic potency against A549, MDA‐MB‐231, KB, KB‐VIN, and MCF7 cell lines with IC₅₀ values ranging from 6.5 to 10.2 μm .     

Pyranochromones from Dictyoloma vandellianum A. Juss and Their Cytotoxic Evaluation

One new chromone 3,3‐dimethylallylspatheliachromene methyl ether ( 1 ), as well as five known chromones, 6‐(3‐methylbut‐2‐enyl) allopteroxylin methyl ether ( 2 ), 6‐(3‐methylbut‐2‐enyl) allopteroxylin ( 3 ), 3,3‐dimethylallylspatheliachromene ( 4 ), 5‐O‐methylcneorumchromone K ( 5 ) and spatheliabischromene ( 6 ), two alkaloids, 8‐methoxy‐N‐methylflindersine ( 7 ) and 8‐methoxyflindersine ( 8 ), and two limonoids, limonin diosphenol ( 9 ) and rutaevin ( 10 ), were isolated from Dictyoloma vandellianum A. Juss (Rutaceae). Cytotoxic activities towards tumor cell lines B16‐F10, HepG2, K562 and HL60 and non‐tumor cells PBMC were evaluated for compounds 1  –  6 . Compound 1 was the most active showing IC₅₀ values ranging from 6.26 to 14.82 μg/ml in B16‐F10 and K562 cell lines, respectively, and presented IC₅₀ value of 11.65 μg/ml in PBMC cell line.     

Composition,Antioxidant, and Cytotoxic Activities of the Essential Oils from Fresh and Air‐Dried Aerial Parts of Pallenis spinosa

This study was performed to determine the chemical composition, antioxidant and cytotoxic effects of essential oils extracted from the aerial parts of fresh (F‐PSEO) and air‐dried (D‐PSEO) Pallenis spinosa. The composition of the oils was analyzed by gas chromatography (GC) and GC/mass spectrometry, the antioxidant activity by free radical scavenging and metal chelating assays, and their cytotoxicity by a flow cytometry analysis. The primary components in both oils were sesquiterpene hydrocarbons and oxygentated sesquiterpenes. F‐PSEO contained 36 different compounds; α‐cadinol (16.48%), germacra‐1(10),5‐diene‐3,4‐diol (14.45%), γ‐cadinene (12.03%), and α‐muurolol (9.89%) were the principal components. D‐PSEO contained 53 molecules; α‐cadinol (19.26%), δ‐cadinene (13.93%), α‐muurolol (12.88%), and germacra‐1(10),5‐diene‐3,4‐diol (8.41%) constituted the highest percentages. Although both oils exhibited a weak radical scavenging and chelating activity, compared to α‐tocopherol and ascorbic acid, D‐PSEO showed a 2‐fold greater antioxidant activity than F‐PSEO. Furthermore, low doses of F‐PSEO were able to inhibit the growth of leukemic (HL‐60, K562, and Jurkat) and solid tumor cells (MCF‐7, HepG2, HT‐1080, and Caco‐2) with an IC₅₀ range of 0.25 – 0.66 μg/ml and 0.50 – 2.35 μg/ml, respectively. F‐PSEO showed a ca. 2 – 3‐fold stronger cytotoxicity against the tested cells than D‐PSEO. The potent growth inhibitory effect of the plant essential oil encourages further studies to characterize the molecular mechanisms of its cytotoxicity.     

Melanogenesis‐Inhibitory and Cytotoxic Activities of Diarylheptanoids from Acer nikoense Bark and Their Derivatives

Nine cyclic diarylheptanoids, 1 – 9 , including two new compounds, i.e., 9‐oxoacerogenin A ( 8 ) and 9‐O‐β‐D ‐glucopyranosylacerogenin K ( 9 ), along with three acyclic diarylheptanoids, 10 – 12 , and four phenolic compounds, 13 – 16 , were isolated from a MeOH extract of the bark of Acer nikoense (Aceraceae). Acid hydrolysis of 9 yielded acerogenin K ( 17 ) and D ‐glucose. Two of the cyclic diarylheptanoids, acerogenin A ( 1 ) and (R)‐acerogenin B ( 5 ), were converted to their ether and ester derivatives, 18 – 24 and 27 – 33 , respectively, and to the dehydrated derivatives, 25, 26, 34 , and 35 . Upon evaluation of compounds 1 – 16 and 18 – 35 for their inhibitory activities against melanogenesis in B16 melanoma cells, induced with α‐melanocyte‐stimulating hormone (α‐MSH), eight natural glycosides, i.e., six diarylheptanoid glycosides, 2 – 4, 6, 9 , and 12 , and two phenolic glycosides, 15 and 16 , exhibited inhibitory activities with 24–61% reduction of melanin content at 100 μM concentration with no or almost no toxicity to the cells (88–106% of cell viability at 100 μM ). In addition, when compounds 1 – 16 and 18 – 35 were evaluated for cytotoxic activity against human cancer cell lines, two natural acyclic diarylheptanoids, 10 and 11 , ten ether and ester derivatives, 18 – 22 and 27 – 31 , and two dehydrated derivatives, 34 and 35 , exhibited potent cytotoxicities against HL60 human leukemia cell line (IC₅₀ 8.1–19.3 μM ), and five compounds, 10, 11, 20, 29 , and 30 , against CRL1579 human melanoma cell line (IC₅₀ 10.1–18.4 μM ).     

Synthesis and Anticancer Activity of 3‐(Substituted Aroyl)‐4‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrrole Derivatives

A series of 3‐(substituted aroyl)‐4‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrrole derivatives were synthesized and determined for their anticancer activity against eleven cancer cell lines and two normal tissue cell lines using MTT assay. Among the synthesized compounds, compound 3f was the most potent compound against A375, CT‐26, HeLa, MGC80‐3, NCI‐H460 and SGC‐7901 cells (IC₅₀ = 8.2 – 31.7 μm ); 3g , 3n and 3a were the most potent compounds against CHO (IC₅₀ = 8.2 μm ), HCT‐15 (IC₅₀ = 21 μm ) and MCF‐7 cells (IC₅₀ = 18.7 μm ), respectively. Importantly, all the target compounds showed no cytotoxicity towards the normal tissue cell (IC₅₀ > 100 μm ). Thus, these compounds with the potent anticancer activity and low toxicity have potential for the development of new anticancer chemotherapy agents.