Synthesis and cytotoxicity of novel podophyllotoxin derivatives

In order to find novel synthetic antitumor agents with superior cytotoxicity and overcoming multidrug resistance,a novel series of 4β-N-substituted podophyllotoxin derivatives were synthesized and evaluated as potential antitumor agents.Seven novel podophyllotoxin derivatives were synthesized by linking 4β-amino-4-deoxypodophyllotoxin with N-substituted 5-methylindol-3- yl-glyoxyl chlorides and tested against K562 and K562/A02 using SRB methods in vitro,KB and KBV using MTT methods in vitro.     

Rotenoids and coumaronochromonoids from Boerhavia erecta and their biological activities: In vitro and in silico studies

Boerhavia erecta is a tropical plant that is widely used in folk medicine. Roots of this plant are applied as a diuretic, stomachic, anthelminthic, febrifuge, and expectorant. The whole plant has been used for treating gastrointestinal, liver, and infertility problems. More than 40 metabolites have been identified in its leaves, roots, and the aerial parts. Among them, isoflavonoids such as rotenoids and coumaronochromonoids are major components. Some of these compounds exhibited potent cytotoxicity, COX inhibition and opioid and cannabinoid receptor. However, little is known about the inhibition of α-glucosidase enzyme of these compounds. As part of our ongoing search for α-glucosidase inhibitors from Vietnamese medicinal plants, we conducted bioactive-guided isolation of the aerial part of Boerhavia erecta. Twelve known compounds were isolated and elucidated, including boeravinone M (1), boeravinone G (2), boeravinone P (3), boeravinone B (4), boeravinone E (5), boeravinone A (6), boeravinone H (7), 9-O-methyl-4-hydroxyboeravinone B (8), boeravinone T (9), boeravinone J (10), boeravinone C (11), and 10-demethylboeravinone C (12). Isolates 2–5, 7, and 12 showed potent α-glucosidase inhibition, which is stronger than acarbose, a positive control. Among them, compound 5 showed strongest inhibition with IC₅₀ value of 85.1 µM. A kinetic study indicated that 5 was a mixed-type inhibitor. Compound 5 was determined to be a potential inhibitor of the α-glucosidase enzyme based on in silico molecular docking mode. Compounds were tested for cytotoxicity against K562 and antimicrobial activity against antibiotic-resistant, pathogenic bacteria Enterococcus faecium, Staphylococcus aureus, and Acinetobacter baumannii. Only compounds 4 and 12 showed moderate activity against K562 cell line. As regards antimicrobial activity, compounds 6 and 10 showed strong inhibition toward Enterococcus faecium. In silico studies of cytotoxicity and antimicrobial activity were also performed, indicating that in vitro and in silico data were consistent.     

Longipedlactones A-I, nine novel triterpene dilactones possessing a unique skeleton from Kadsura longipedunculata

Nine novel triterpene dilactones with an unprecedented rearranged pentacyclic skeleton, longipedlactones A-I (1-9), have been isolated from the leaves and stems of Kadsura longipedunculata Finet et Gagnep (Schisandraceae). Their structures were determined on the basis of comprehensive spectroscopic analysis and single-crystal X-ray structure determination. A biogenetic pathway for longipedlactone A (1) was also proposed. Compounds 1-3, 6, and 8 showed significant cytotoxicity against A549, with HT-29 and K562 cell lines having IC₅₀ values of 0.84-11.38 μM in vitro.     

Kadcoccilactones K-R, triterpenoids from Kadsura coccinea

Phytochemical investigation on the stems of Kadsura coccinea led to the isolation of 8 new triterpenoids, kadcoccilactones K-R (1-8), and 10 known analogues. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compounds 1-3 characterized with an aromatic ring E in their molecules are rarely naturally occurred kadlongilactone derivatives. Moreover, all compounds were evaluated for their inhibitory activity against K562, Bel-7402, and A549 human tumor cells. Compounds 9 and 10 exhibited potent cytotoxicity against K562, Bel-7402, and A549 cell lines with IC₅₀ values less than 0.1, 0.1, and 1.0 μm, respectively.     

Euphorane C,an unusual C17-norabietane diterpenoid from Euphorbia dracunculoides induces cell cycle arrest and apoptosis in human leukemia K562 cells

Four new polycyclic diterpenoids euphoranes A ? D (1–4), together with 12 known terpenoids (5–16) were isolated from the whole plants of Euphorbia dracunculoides. Compound 2 represents the first example of aromatic 15,16,17-trinorabietane diterpenoid in Euphorbia species, and euphorane C (3) is an unusual 17-norabietane diterpenoid. The absolute configurations of 1, 2, and 4 were determined by single crystal X-ray diffraction, while that of 3 was established with the aid of ECD and 1D NMR quantum chemical calculation. Moreover, the absolute stereochemistry of 11 was demonstrated for the first time by crystallographic data. Compounds 1–16 were screened for antiproliferative activities against five human cancer cell lines, and 3 showed significant cytotoxicity against the human leukemia K562 cells with IC₅₀ value of 3.59 μM. Preliminary mechanistic investigation revealed that 3 could induce cell cycle arrest at G0/G1 phase and apoptosis in K562 cells.     

Cytotoxic ent-kauranoid derivatives from Isodon rubescens

An extensive study of the diterpenoids produced by the species of Isodon rubescens, has led to the isolation of 12 new ent-kaurane diterpenoids, hebeirubescensins A-L (1-12), and 19 known analogues. Their structures were determined on the basis of spectroscopic analysis. Selected compounds were assayed for their inhibitory ability against human A549, HT-29, and K562 cells. Among them, hebeirubescensins B and C exhibited significant cytotoxicity with IC₅₀ values of <2.0 μM. The structure-activity relationships were discussed.     

Palladium(II)-catalyzed enyne cyclization strategies toward the podophyllotoxin ring system

A functionally enriched ABCD ring system of podophyllotoxin was generated through Pd(II)-templated cyclization of an alkynoic alkene, prepared in five steps from commercially available 6-bromopiperonal. This research expands upon the recent carboesterification methodology of Dong et al. (Angew. Chem., Int. Ed. 2009, 48, 9690–9692) by the application of PdCl₂(MeCN)₂, LiCl, and CuCl₂ conditions, which yielded the desired podophyllotoxin scaffold with an embedded vinyl chloride moiety. Likewise, these conditions were successfully applied to a propargylic alkene prepared in three steps from 6-bromopiperonal. The resulting product contains the ABCD ring system of podophyllotoxin, but substitutes a D-ring furan for the D-ring lactone. Application of the recent methodology of Lu et al. (J. Org. Chem. 1995, 60, 1160–1169) on a related 1,6-enyne substrate led to functionalized α-methylene γ-butyrolactones instead (Pd₂(dba)₃·CHCl₃, LiBr, and CuBr₂). The latter conditions applied to an alkynoic alkene afforded the ABCD ring system of podophyllotoxin with a vinyl bromide group. These vinyl halides allow for derivatization at a critical juncture in order to access novel podophyllotoxin analogs.     

Chemical-epigenetic method to enhance the chemodiversity of the marine algicolous fungus, Aspergillus terreus OUCMDZ-2739

Four new meroterpenoids identified as (R)-4-((2,2-dimethylchroman-6-yl)methyl)-3-(4-hydroxyphenyl)-5-methoxyfuran-2(5H)-one (1), 1-(2,2-dimethylchroman-6-yl)-3-(4-hydroxyphenyl)propan-2-one (2), (R,E)-3-(2,2-dimethylchroman-6-yl)-4-hydroxy-5-((2-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl)methylene)furan-2(5H)-one (3), methyl (R)-2-(2-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl) acetate (4), along with nine known compounds (5–13) were isolated from a chemical-epigenetic culture of Aspergillus terreus OUCMDZ-2739 with 10 μM trichostatin A (TSA). Under the same condition without TSA, A. terreus OUCMDZ-2739 produced different compounds (14–20), supporting that the chemical-epigenetic modification of fungi could enrich the chemodiversity of the fungal products. The cytotoxicity was observed for compound 8 against K562 cell, 9 against MCF-7 and K562 cells and 12 against MCF-7 cell with IC₅₀ values of 9.5, 10.1, 13.0 and 8.5 μM, respectively. Compounds 3, 8 and 17 exhibited stronger α-glucosidase inhibition than 1-deoxynojirimycin and acarbose (positive controls) with IC₅₀ values of 24.8, 1.2, 61.6, 191.7 and 555.1 μM, respectively. The enzyme kinetics study further indicated that compound 8 was an anticompetitive inhibitor with K_i value of 1.42 μM.     

Synthesis of podophyllotoxin analogues: δ-lactone-containing picropodophyllin, podophyllotoxin and 4′-demethyl-epipodophyllotoxin derivatives

Non-epimerizable cis and trans δ-lactone analogues of podophyllotoxin have been prepared. Thus the synthesis of the cis isomer 4 has been achieved in 8 steps and 4% overall yield from podophyllotoxin 1 via the reduction of the γ lactone ring into the trans diol, selective protection of the 4-OH and 11-OH as a benzylidene acetal, and Wittig elongation at C-13 with inversion of configuration at C-2. Same elongation at C-13 but via the formation of a mesylate and introduction of a cyano group, led to the trans δ-lactone 5 (7 steps from 1 and 6% overall yied) with a small amount of its C-4 epimer 6. The synthesis of non-epimerizable δ-lactone analogues of 4′-demethyl-epipodophyllotoxin 7 and of 4-demethyl podophyllotoxin 8 are also reported. The synthesis of 7 and 8 was based upon the reduction of the γ-lactone ring of 4′-demethyl-4-epipodophyllotoxin followed by selective protection at C-11 and elongation at C-13. (8-15% and 4% overall yields). Compounds 4, 5 and 7 did not display relevant cytotoxicity in vitro against L1210 murine leukemia.     

Dictyoneolone,a B/C ring juncture-defused steroid from a Dictyonella sp. sponge

Dictyoneolone (1), a new secosteroid was isolated from a Dictyonella sp. sponge collected from Gageo-do, Korea. Based upon the results of combined spectroscopic analyses, the structure of this compound was determined to possess a highly unusual B/C ring juncture-defused moiety. The configurations of 1 were determined by a combination of proton-proton couplings and NOESY analyses. Dictyoneolone exhibited weak cytotoxicity against the K562 and A549 cancer cell lines.     

Design and synthesis of novel cytotoxic podophyllotoxin derivatives

<正>In order to investigate the effect of different C4 linkage moieties on the cytotoxicity of podophyllotoxin derivatives,novel 4-Nand 4-C-substituted 4'-O-demethylepipodophyllotoxin derivatives were designed and synthesized.All the compounds were tested against A549 and MCF-7 tumor cells in vitro,and six compounds showed significant cytotoxicity.The most active compound 9f was superior to GL-331,and exhibited potent cytotoxicity with IC_(50) value at 10~(-7) mol/L level.     

Antitumour tiazofurin analogues embedded with an amide moiety at the C-2′ position

Synthesis of four new tiazofurin analogues has been accomplished starting from d-glucose. The key step of the synthesis was the three-step cascade that enabled an efficient hydrogen sulfide mediated one-pot conversion of 2-azido-3-O-acyl-ribofuranosyl cyanides to the corresponding 2-alkylamido ribofuranosyl thiocarboxamides. The resulting key intermediates were first converted to protected tiazofurin derivatives by cyclocondensation with ethyl bromopyruvate, and finally to target C-nucleosides by treatment with ammonia in methanol. In vitro cytotoxicities of tiazofurin analogues against a number of human tumour cell lines were recorded and compared with those observed for the parent molecule (tiazofurin), as well as the commercial antitumour agent doxorubicin (DOX). Analogues 2b-d have shown a potent in vitro cytotoxic activity against human myelogenous leukaemia K562. Among solid tumour cell lines, HT29 was sensitive only to 2d, while HeLa cells were sensitive to 2a, 2b and 2d. Only analogue 2a was highly cytotoxic against MCF-7 cells. No tiazofurin analogue exhibits any significant cytotoxicity towards normal foetal lung MRC-5 cells. Downregulation of Bcl-2, activation of caspase-3 and presence of cleavage product of PARP suggest that the cytotoxic effects of tiazofurin analogues 2a-d in K562 might be mediated by apoptosis in a caspase-dependent way. On the contrary, tiazofurin did not induce apoptosis of K562 cells, which suggests a different mechanism of action, most probably through the inhibition of IMPDH. Flow cytometry and Western blot analysis data agreed well with the results of MTT assay, and enabled identification of analogue 2c as the most promising antitumour agent that preferentially target cancer cells over normal cells and thus represents a new lead for further optimization.     

One-pot green synthesis and cytotoxicity of new <Emphasis Type="Italic">α</Emphasis>-aminophosphonates

A novel series of α-aminophosphonates containing the trifluoromethyl aniline moiety were obtained in high yields by condensation of 2-methyl-3-trifluoromethyl aniline, aryl/heteroaryl aldehydes and dimethylphosphite in the presence of chitosan as a catalyst. The molecular modeling studies revealed their important structural features of binding affinities towards the target enzyme. The cytotoxicity of these compounds was evaluated against PC-3(prostate cancer), MCF-7 (breast cancer), HeLa(cCervix Cancer), U973, K562 and HL60 human lLeukemia cell lines. Compound 4k with a pyrene moiety showed high potency against a breast cancer cell line, while compounds 4g and 4k exhibited more promising cytotoxicity against U973, K562 and HL60 cell lines.     

Symmetric and asymmetric ent-kaurane dimers isolated from Isodon japonicus

Bisjaponins A (1) and B (2), two new dimeric ent-kaurane diterpenoids connected with a rare four-membered carbon ring, which was formed by [2+2] reaction, were isolated from the aerial parts of Isodon japonicus. Their structures were elucidated by the analysis of spectroscopic evidence including extensive 2D NMR and MS data. Both the compounds were inactive for their cytotoxicity against human tumor cell lines, K562 and HepG2.     

COX-2 and JAK3 inhibitory meroterpenoids from the mushroom Ganoderma theaecolum

Ganoderma mushrooms possess antioxidant, anticancer, and immunomodulatory properties. In this study, eleven new meroterpenoids, ganotheaecolumols A-K (1–6, 10,11, 13, 14, and 17), together with nine known ones (7–9, 12, 15, 16, and 18–20) were isolated from the fruiting bodies of G. theaecolum. Their structures were elucidated by spectroscopic and computational methods. All the new compounds and iso-ganotheaecolumol I (12) were tested for their inhibitory activities against COX-2 and JAK3 kinases, and cytotoxic effects. It was found that most meroterpenoids could inhibit COX-2 and JAK3 with compounds 3, 4, 12, 13, and 17 having IC₅₀ values of 1.05?±?0.10, 1.38?±?0.11, 2.61?±?0.79, 3.47?±?0.58, and 4.84?±?0.60?μM towards COX-2. Whereas, none of the test compounds exhibited cytotoxic effects against human cancer cells (K562, A549, and Huh-7).     

A cytotoxic pyrrolidinoindoline diketopiperazine dimer from the algal fungus Eurotium herbariorum HT-2

A new cytotoxic pyrrolidinoindoline diketopiperazine dimer, cristatumin E （1）, was isolated from the fermentation broth of the algal fungus Eurotium herbariorum HT-2 associated with the marine algae, Enteromorpha prolifera. The structure was determined by spectroscopic analyses and Marfey＇s amino acid analysis. Cristatumin E （1） showed cytotoxicity against K562 tumor cell line and antibacterial activity against Enterobacter aerogenes and Escherichia coli with IC50 and MIC values of 8.3, 44.0 and 44.0 μmol/L, respectively.     

Pre-schisanartanins C-D and propintrilactones A-B, two classes of new nortriterpenoids from Schisandra propinqua var. propinqua

Four new nortriterpenoids, pre-schisanartanins C and D (1-2) with pre-schisanartane backbone, and propintrilactones A and B (3-4) possessed wuweiziartane framework, were isolated from the acetone extract of the stems of Schisandra propinqua var. propinqua. Their structures were characterized by extensive spectroscopic analyses. Compounds 3 and 4 existed as a pair of slowly interconverting diastereomers at room temperature; their absolute configuration was established by CD methods. Compounds 1-4 showed no cytotoxicity against K562, A549, and HT-29 human cancer cells.     

Preparation and cis-to-trans transformation study of square-planar [Pt(Ln)2Cl2] complexes bearing cytokinins derived from 6-benzylaminopurine (Ln) by view of NMR spectroscopy and X-ray crystallography

Mononuclear, square-planar platinum(II) complexes involving derivatives of aromatic cytokinins as the ligands, and having the general formula cis-[Pt(L_n)₂Cl₂] (1–3) and trans-[Pt(L_n)₂Cl₂] (4–6), where n = 1–3, L₁ = 2-chloro-6-(benzylamino)-9-isopropylpurine, L₂ = 2-chloro-6-[(4-methoxybenzyl)amino]-9-isopropylpurine and L₃ = 2-chloro-6-[(2-methoxybenzyl)-amino]-9-isopropylpurine, have been synthesized and characterized by elemental analysis, MALDI-TOF mass, FT IR, ¹H, ¹³C, ¹⁵N and ¹⁹⁵Pt NMR spectral measurements. Dynamic cis-to-trans isomerization process of complex 1 in N,N′-dimethylformamide (DMF) has been investigated by means of multinuclear NMR spectroscopy. The solid-state structures of 1, 4 · (DMF)₂, and 5 have been determined by single crystal X-ray analysis. X-ray structures revealed that the heterocyclic ligands are coordinated to platinum via nitrogen atom N(7) in all the complexes studied. In vitro cytotoxicity of the prepared complexes against MCF7, G361, K562, and HOS has been evaluated. Owing to low solubility of the complexes in water, the cytotoxicity has been only tested up to 5 μM concentration. Unfortunately, all complexes have been found to be non-cytotoxic in the accessible concentration range.     

Three new dibromopyrrole alkaloids from the South China Sea sponge Agelas nemoechinata

Three new dibromopyrrole alkaloids, 9-N-methylcylindradine A (1), 1-N-methylugibohlin (2), nemoechine H (3), together with one known dibromopyrrole alkaloid N-methyldibromoisophakellin (4) were isolated from the South China Sea sponge Agelas nemoechinata. Their structures were elucidated by comprehensive spectroscopic methods including HRESIMS and NMR, and the absolute configuration of compound 1 was further confirmed by comparison of optical rotation. Compound 3 exhibited moderate cytotoxic activity against K562 and L-02 with IC₅₀ values of 6.1 μM and 12.3 μM, respectively.     

Cytotoxic Podophyllotoxin Type-Lignans from the Steam Bark of <em>Bursera fagaroides </em>var. <em>fagaroides</em>

The hydroalcoholic extract of the steam bark of B. fagaroides var. fagaroides displayed potent cytotoxic activity against four cancer cell lines, namely KB (ED₅₀ = 9.6 × 10^-2 μg/mL), PC-3 (ED₅₀ = 2.5 × 10^-1 μg/mL), MCF-7 (ED₅₀ = 6.6 μg/mL), and HF-6 (ED₅₀ = 7.1 × 10^-3 μg/mL). This extract also showed anti-tumour activity when assayed on mice inoculated with L5178Y lymphoma cells. Bioactivity-directed isolation of this extract, afforded seven podophyllotoxin-type lignans identified as podophyllotoxin (1), β-peltatin-A-methylether (2), 5'-desmethoxy-β-peltatin-A-methylether (3), desmethoxy-yatein (4), desoxypodophyllotoxin (5), burseranin (6), and acetyl podophyllotoxin (7) by 1D and 2DNMR and FAB-MS analyses, and comparison with reported values. All the isolated compounds showed potent cytotoxic activity in the cell lines tested, especially compound 3, which exhibited greater activity than camptothecin and podophyllotoxin against PC-3 (ED₅₀ = 1.0 × 10^-5 μg/mL), and KB (ED₅₀ = 1.0 × 10^-5 μg/mL). This is the first report of the isolation of podophyllotoxin and its acetate in a Bursera species.