In vitro cytotoxicity on human ovarian cancer cells by T-type calcium channel blockers

The growth inhibition of human cancer cells via T-type Ca²⁺ channel blockade has been well known. Herein, a series of new 3,4-dihydroquinazoline derivatives were synthesized via a brief SAR study on KYS05090 template and evaluated for both T-type Ca²⁺ channel (Ca_v3.1) blockade and cytotoxicity on three human ovarian cancer cells (SK-OV-3, A2780 and A2780-T). Most of compounds except 6i generally exhibited more potent cytotoxicity on SK-OV-3 than mibefradil as a positive control regardless of the degree of T-type channel blockade. In particular, eight compounds (KYS05090, 6a and 6c–6h) showing strong channel blockade exhibited almost equal and more potent cytotoxicity on A2780 when compared to mibefradil. On A2780-T paclitaxel-resistant human ovarian carcinoma, two compounds (KYS05090 and 6d) were 20-fold more active than mibefradil. With respect to cell cycle arrest effect on A2780 and A2780-T cells, KYS05090 induced large proportion of sub-G₁ phase in the cell cycle progression of A2780 and A2780-T, meaning the induction of cancer cell death instead of cell cycle arrest via blocking T-type Ca²⁺ channel. Among new analogues, compounds 6g and 6h induced cell cycle arrest at G₁ phase of A2780 and A2780-T cells in dose-dependent manner and exhibited strong anti-proliferation effects of ovarian cancer cells by blocking T-type Ca²⁺ channel. Furthermore, 6g and 6h possessing strong cytotoxic effects could induce apoptosis of A2780 cells, which was detected by confocal micrographs using DAPI staining.     

Cytotoxic macrocyclic diterpenoids from Jatropha multifida

Nine new macrocyclic diterpenoids (1–9), jatromultones A-I, along with eight known analogues (10–17) were isolated from the trunks of Jatropha multifida. The structures of the new compounds, including their absolute configurations, were elucidated by combination of spectroscopic analysis, single crystal X-ray diffraction, Rh₂(OCOCF₃)₄-induced CD method, and chemical correlations. All compounds were screened for the cytotoxicity against five cancer cell lines, including one drug-resistant cell line, and seven compounds exhibited significant activity with IC₅₀ values less than 10 μM. Compound 4 with IC₅₀ values ranging from 2.69 to 6.44 μM toward all cell lines was selected for further mechanistic study, which showed that 4 could arrest cell cycle at G2/M phase and induce apoptosis. The brief structure-activity relationships (SARs) of these macrocyclic diterpenoids were also discussed.     

Phenanthroimidazole derivatives act as potent inducer of autophagy by activating DNA damage pathway

A series of imidazo[4,5f][1,10]phenanthroline derivatives (1–6) have been synthesized in this study, and their inhibitory activity was evaluated by MTT assay. Results showed that all of these compounds demonstrate a promising inhibitory activity against a panel of human cancer cell lines. The 6, the most effective compound with IC₅₀ of approximately 2.3 ± 0.1 µM, was against the growth and could induce autophagy of HepG2 cells. This condition was confirmed by abundant autophagic vacuoles appearing in cells and evident ultrastructural changes observed under transmission electron microscopy. The autophage induced by 6 has also been demonstrated by up-regulating LC3-II and Beclin1. The apoptosis and G2/M phase cell cycle arrest through DSB damage have also been confirmed after the HepG2 cells were treated by 6. These multiple effects, especially induction apoptosis and autophagy, indicate the potential of 6 for development as a novel anticancer drug.     

Synthesis and antitumor activity of novel enediyne-linked pyrrolo[2,1-c][1,4]benzodiazepine hybrids

A series of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) hybrids linked with enediyne is described. These compounds were prepared by linking C-8 of DC-81 (1) with an enediyne (10–16) through carbon chain linkers to afford PBD hybrid agents 17–23 in good yields. Most of the hybrids on human cancer cell lines exhibited higher cytotoxicity, and an increase in the sub-G1 population than 1. In a previous article, we have demonstrated that DC-81-indole conjugate agents (3–6) are potent inducers of cell apoptosis in melanoma. In the present article, we investigated whether DC-81-enediyne agents possess more cytotoxicity than 6 on human 293T cells. Our data revealed that treatment of 293T cells with DC-81-enediyne resulted in a significant increase of annexin V binding, caspase-3 degradation, and p53 arrest to identify apoptotic cells than 6. These results suggest that the DC-81-enediyne agents are more efficient in inducing apoptosis than DC-81-indole in 293T cells.     

Novel lawsone-containing ruthenium(II) complexes: Synthesis,characterization and anticancer activity on 2D and 3D spheroid models of prostate cancer cells

This study describes a series of newly synthesized phosphine/diimine ruthenium complexes containing the lawsone as bioligand with enhanced cytotoxicity against different cancer cells, and apoptosis induction in prostatic cancer cells DU-145. The complexes [Ru(law)(N-N)₂]PF₆ where N-N is 2,2′-bipyridine (1) or 1,10-phenanthroline (2) and [Ru(law)(dppm)(N-N)]PF₆, where dppm means bis(diphenylphosphino)methane, N-N is 2,2′-bipyridine (3) or 1,10-phenanthroline (4), and law is lawsone, were synthesized and fully characterized by elemental analysis, molar conductivity, NMR, UV–vis, IR spectroscopies and cyclic voltammetry. The interaction of the complexes (1–4) with DNA was evaluated by circular dichroism, gel electrophoresis, and fluorescence, and the complexes presented interactions by the minor grooves DNA. The phosphinic series of complexes exhibited a remarkably broad spectrum of anticancer activity with approximately 34-fold higher than cisplatin and 5-fold higher than doxorubicin, inhibiting the growth of 3D tumor spheroids and the ability to retain the colony survival of DU-145 cells. Also, the complex (4) inhibits DU-145 cell adhesion and migration potential indicating antimetastatic properties. The mechanism of its anticancer activity was found to be related to increased reactive oxygen species (ROS) generation, increased the BAX/BCL-2 ratio and subsequent apoptosis induction. Overall, these findings suggested that the complex (4) could be a promising candidate for further evaluation as a chemotherapeutic agent in the prostate cancer treatment.     

Synthesis and biological evaluation of isoprenylated coumarins as potential anti-pancreatic cancer agents

A series of isoprenylated coumarins has been designed, synthesized, and evaluated against human pancreatic adenocarcinoma cell line PANC-1 under nutrient-rich and nutrient-deprived conditions. The compounds described investigate the effect of isoprenyl chain length and positioning on cell growth inhibition. The majority of these compounds displayed cytotoxicity against PANC-1 cells selectively in the absence of essential amino acids, glucose, and serum, and showed no cytotoxicity under nutrient-rich conditions. In this study, compound 6 exhibited the highest cytotoxic activity with an LC₅₀ value of 4 μM and induced apoptosis-like morphological changes in PANC-1 cells after a 24-h incubation. The evaluated structure–activity relationships show that substitution at the 6-position and the presence of a farnesyl isoprenyl tail are important structural features for enhanced preferential cytotoxicity. These findings provide important information to designing other structural analogues for potential application as novel pancreatic antitumor agents.     

Synthesis and biological evaluation of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides as antimitotic agents

A library of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides (7a–al) have been designed, synthesized and screened for their anti-proliferative activity against some selected human cancer cell lines namely DU-145, A-549, MCF-7 and HeLa. Most of them have shown promising cytotoxicity against lung cancer cell line (A549), amongst them 7f was found to be the most potent anti-proliferative congener. Furthermore, 7f exhibited comparable tubulin polymerization inhibition (IC₅₀ value 2.04 µM) to the standard E7010 (IC₅₀ value 2.15 µM). Moreover, flow cytometric analysis revealed that this compound induced apoptosis via cell cycle arrest at G₂/M phase in A549 cells. Induction of apoptosis was further observed by examining the mitochondrial membrane potential and was also confirmed by Hoechst staining as well as Annexin V-FITC assays. Furthermore, molecular docking studies indicated that compound 7f binds to the colchicine binding site of the β-tubulin. Thus, 7f exhibits anti-proliferative properties by inhibiting the tubulin polymerization through the binding at the colchicine active site and by induction of apoptosis.     

Topoisomerase II inhibitors from the roots of Stellera chamaejasme L.

Three new compounds, including one daphnane diterpene (1), one sesquiterpene (6), and one lignan (7) have been isolated from the Stellera chamaejasme L., together with five other known compounds, including four daphnane diterpenenoids (2–5) and one lignan (8). The structures of the new compounds were elucidated by spectroscopic analysis. The cytotoxicities of compounds 1–8 towards human lung adenocarcinoma cells (A549 cells) were evaluated using a sulforhodamine B assay. All of the compounds displayed significant cytotoxicity, with IC₅₀ values in the ranging of 0.2 nM to 2.0 μM. Mechanistic studies revealed that the antitumor activities of compounds 1–3 and 7 were derived from their inhibition of topoisomerase II (Topo II). Furthermore, as a Topo II inhibitor, compound 1 was found to effectively induced G2-M phase cell cycle arrest and apoptosis in cancer cells.     

Cytotoxic scalarane sesterterpenes from a Korean marine sponge Psammocinia sp.

Three novel scalarane sesterterpenes were isolated from a Korean marine sponge, Psammocinia sp., along with four known derivatives. Their structures were elucidated on the basis of NMR, MS and IR spectroscopic data. The three new compounds are 12-deacetoxy-23-hydroxyscalaradial (1), 12-dehydroxy-23-hydroxyhyrtiolide (2) and 12-O-acetyl-16-deacetoxy-23-acetoxyscalarafuran (3), respectively, and the four known compounds are 12-deacetoxy-23-hydroxyheteronemin (4), 12-deacetoxy-23-acetoxy-19-O-acetylscalarin (5), 12-deacetoxy-23-O-acetoxyheteronemin (6) and 12-deacetoxyscalaradial (7). They exhibited cytotoxicity against intractable human cancer cell lines A498, ACHN, MIA-paca and PANC-1, with an IC₅₀ range of 0.4–48 μM.     

Click chemistry based multicomponent approach in the synthesis of spirochromenocarbazole tethered 1,2,3-triazoles as potential anticancer agents

A series of spirochromenocarbazole tethered 1,2,3-triazoles were synthesized via click chemistry based one-pot, five component reaction between N-propargyl isatins, malononitrile, 4-hydroxycarbazole, aralkyl halides and sodium azide using cellulose supported CuI nanoparticles (Cell-CuI NPs) as the heterogeneous catalyst. Antiproliferative activity of all the synthesized compounds was investigated against panel of cancer cell lines such as MCF-7, MDA-MB-231, HeLa, PANC-1, A-549, and THP-1. Many of the synthesized compounds exhibited good anti-proliferative activity against breast (MCF-7 and MDA-MB-231) and cervical (HeLa) cancer cells with IC₅₀ values less than 10 μM. In case of MCF-7 cells, among the nine compounds that showed good anti-proliferative activity, compounds 6f and 6j were found to be highly potent (IC₅₀ = 2.13 μM and 4.80 μM, respectively). In case of MDA-MB-231, three compounds (6k, 6j and 6s) showed antiproliferative activity amongst which 6k was the most potent one (IC₅₀ = 3.78 μM). On the other hand, in cervical cancer HeLa cells, compounds 6b, 6g, 6s and 6u showed excellent antiproliferative activity (IC₅₀ = 4.05, 3.54, 3.83, 3.35 μM, respectively). All the compounds were found to be nontoxic to the human umbilical vein endothelial cells (HUVECs). AO and EtBr staining and fluorescence microscopy studies of the active compounds (IC₅₀ < 5 μM) suggested that these compounds induce cell death by apoptosis.     

Lactones from the pericarps of Litsea japonica and their anti-inflammatory activities

Five new lactones, litsenolide F₁ (1), lisealactone H₁ (10), lisealactone H₂ (11), akolactone D (13), and akolactone E (14), along with thirteen known compounds were isolated from the pericarps of Litsea japonica (Thunb.) Jussieu. Their chemical structures were elucidated by extensive spectroscopic analyses, including 1D and 2D NMR, HRMS, and chemical methods. The isolated compounds were evaluated for their inhibitory effects on NO production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Among them, 2-alkylidene-3-hydroxy-4-methylbutanolide derivatives (compounds 1–9) exhibited the most potent activity, with IC₅₀ values in the range of 2.9–12.8?μM. In additon, compounds 1, 3, 4, and 6 showed inhibition of iNOS and COX-2 expression in concentration-dependent manner. Compound 3 suppresses mRNA expression of iNOS, COX-2, IL-6, and TNF-α in LPS-stimulated RAW264.7 cells. Based on these evidence, the isolated lactones from L. japonica could be promissing candidates for the development of new anti-inflammatory agents.     

Pyran-2-one derivatives from Croton crassifolius as potent apoptosis inducers in HepG2 cells via p53-mediated Ras/Raf/ERK pathway

Chemical investigation of the roots of Croton crassifolius led to the isolation of five pyran-2-one derivatives, including two brand new compounds (1–2), one new natural product (3) and two known compounds (4–5). Their structures and absolute configurations were established by spectroscopic analyses as well as comparison between the calculated optical rotation (OR) values with the experimental data. Interestingly, the new compound 1 showed an unusual negative chemical shift at H-11. It is well known that negative chemical shift values of ¹H NMR spectrum are extremely rare in natural products. Such a negative chemical shift of ¹H NMR spectrum was reproduced by density functional theory (DFT) calculations and explained by the shielding effect from the pyran-2-one ring over the hydrogen atom in the 3D conformations. Then, MTT assay was applied to evaluate the cytotoxicity of the isolated compounds (1–5) against two liver cancer cell lines (HepG2 and MHCC97H). The results suggested that compound 1 displayed the highest cytotoxicity with an IC₅₀ value of 9.8 μM against HepG2 cells. Moreover, there was no obvious cytotoxicity of compounds 1–5 on normal liver cell line LO2. Furthermore, the mechanism of apoptosis induction in compound 1-treated HepG2 cells was investigated. The results showed that compound 1 could induce apoptosis via p53-mediated Ras/Raf/ERK suppression in HepG2 cells.     

Synthesis of pyrazolo[1,5-a]pyrimidine linked aminobenzothiazole conjugates as potential anticancer agents

A series of pyrazolo[1,5-a]pyrimidine linked 2-aminobenzothizole conjugates (6a–t) were synthesized and evaluated for their anticancer activity against five human cancer cell lines. Among them two compounds 6p and 6m showed significant anticancer activity with IC₅₀ values ranging from 2.01 to 7.07 and 1.94–3.46 μM, respectively. Moreover, cell cycle arrest in G₂/M and reduction in Cdk1 expression level were observed upon treatment of these compounds and they also induced caspase-3 dependent apoptosis. This was further confirmed by staining as well as DNA fragmentation analysis.     

Chemical constituents of Callistemon citrinus from Egypt and their antiausterity activity against PANC-1 human pancreatic cancer cell line

Human pancreatic cancer is resistant to almost all conventional chemotherapeutic agents. It is known to proliferate aggressively within hypovascular tumor microenvironment by exhibiting remarkable tolerance to nutrition starvation,  a phenomenon termed as “austerity”. Search for the new agents that eliminate the tolerance of cancer cells to nutrition starvation is a promising strategy in anticancer drug discovery. In this study, two new meroterpenoids named callistrilones O and P (1 and 2) together with eight known triterpenes (3–10) were isolated from the active dichloromethane extract of Callistemon citrinus leaves. The structure elucidation of the new compounds was achieved by HRFABMS, 1D, 2D NMR, and ECD quantum calculations. All isolated compounds were tested for their preferential cytotoxicity against PANC-1 human pancreatic cancer cells. Among these, callistrilone O (1) exhibited the most potent preferential cytotoxicity with a PC₅₀ value of 0.3 nM, the strongest activity with over 2000 times potent than the positive control arctigenin. Callistrilone O (1) induced dramatic alterations in PANC-1 cell morphology leading to cell death under nutrient-deprived conditions. Compound 1 also inhibited PANC-1 cell migration and -PANC-1 colony formation under the nutrient-rich condition.     

Glycosyl glycerides from the aerial parts of Malva verticillata and their chemopreventive effects

A new glycosyl glyceride (5) along with twelve known ones (1–4 and 6–13) including two sulfoquinovosyl glycerides (1 and 2) were isolated from the aerial parts of Malva verticillata. Based on several spectroscopic methods, compound 5 was identified to be (2S)-1-O-β-d-galactopyranosyl-3-O-isostearoyl glyceride, and named malvaglycolipid A. Compounds 1 and 2 contained a unique sugar, (6-deoxy-6-sulfo)-α-d-glucopyranose, which very rarely occurs in natural sources. This is the first report for the isolation of compounds 1 and 2 from natural sources and the structure determination using NMR experiment. It was also of note that no glycosyl glyceride has previously been isolated from the family of Malvaeae. Most glycosyl glycerides showed cytotoxicity to HepG2, AGS, HCT-15, and A549 human cancer cells. Especially, compounds 1, 2, and 11 exhibited significant cytotoxicity to AGS cells, with IC₅₀ values of 33.7 ± 0.64 μM, 11.1 ± 0.07 μM, and 10.6 ± 0.10 μM, respectively. The n-BuOH fraction and compounds 1, 2, and 11 increased the number of apoptotic cells in the Tali assay and had a significant effect on the levels of proteins related to apoptosis including PARP, caspase-3, Bcl-2, Bax, and β-actin.     

Two new 1,4-naphthoquinone derivatives from Impatiens balsamina L. flowers

Two new 1,4-naphthoquinone derivatives, balsaminone D (1), balsaminone E (2) along with two known compounds (3 and 4) were discovered from Impatiens balsamina L. flowers. Their structures were identified with spectroscopic methods including HR–EI–MS, 1D and 2D NMR, as well as the absolute configuration was determined by ECD calculation. In addition, new compounds 1 and 2 with IC₅₀ value of 30.54 and 40.67 μg/mL exhibited better activities against activated t-HSC/Cl-6 cells than positive control Silymarin and Fufang Biejia Ruangan Pian, of which the IC₅₀ value were 202.34 and 231.56 μg/mL, respectively.     

Phytochemical and cytotoxic studies on the leaves of Calotropis gigantea

A new lignan, 9′-methoxypinoresinol (1), and two new glycosylated 5-hydroxymethylfurfurals, calofurfuralside A (2), and calofurfuralside B (3), together with nine known compounds (4–12) have been isolated from the active fractions, CHCl₃ (IC₅₀, 0.32 μg mL^?1) and EtOAc (IC₅₀, 0.55 μg mL^?1) fractions of the leaves of Calotropis gigantea. Their structures were elucidated based on NMR and MS data. Among the isolated compounds, compounds 1 and 9 exhibited potent cytotoxicity against PANC-1 human pancreatic cancer cell line under the normoglycemic condition with IC₅₀ values of 3.7 and 3.3 μM, respectively. 9′-Methoxypinoresinol (1) significantly inhibited the colony formation of PANC-1 cells in a concentration-dependent manner.     

Vieloplains A-G,seven new guaiane-type sesquiterpenoid dimers from Xylopia vielana

Seven new guaiane-type sesquiterpene dimers vieloplains A-G, connecting patterns through three different direct CC bonds compounds 1–5 (C-3 to C-3′, C-4 to C-1′), compound 6 (C-2 to C-3′, C-4 to C-2′) and compound 7 (C-2 to C-1′, C-4 to C-2′) were isolated from the roots of Xylopia vielana. Their absolute configurations were established by NOESY analysis, the Cu Kα X-ray crystallographic the experiment circular dichroism (ECD) and the calculated ECD. Among them, only compound 6 showed a considerable cytotoxicity against DU145 cells with IC₅₀ values of 9.5 μM. Flow cytometry analysis confirmed that 6 caused death of DU145 cells via apoptosis induction.     

Meeting organometallic chemistry with drug discovery: CH activation enabled discovery of a new ring system of 12H-Indazolo[2,1-a]cinnolin-12-ones with anti-proliferation activity

A diverse library of new ring system 12H-indazolo[2,1-a]cinnolin-12-ones have been synthesized efficiently via Ru (II) and Rh (III) catalyzed tandem CH alkylation/[4 + 2] annulation with diazo compounds in high to excellent yields. For the first time, we evaluated the biological activity of these compounds with this new skeleton and found some compounds exhibited high cytotoxic activity against human PC-3 and PANC-1 tumor cell lines with nanomolar IC₅₀. Among them, the most potent compound 36 showed broad-spectrum cytotoxic activities against a series of human tumor cell lines derived from different organs (IC₅₀ ~ 41 to 197 nM). Moreover, preliminary mechanistic studies indicated that 36 could inhibit the colony formation, cause cell cycle arrest and induce apoptosis of PC-3 cancer cells in a dose-dependent manner. Further intracellular mechanisms investigation found that 36 treatments could dose-dependently decrease the levels of caspase-3 and PARP and up-regulate the level of cleaved PARP. These results suggested that 36 is a novel compound with good potential in the treatment of human cancers and worthy of further investigation.     

Synthesis,biological evaluation and SAR of naftopidil-based arylpiperazine derivatives

For the development of potential anti-prostate cancer agents, 24 kinds of novel naftopidil-based arylpiperazine derivatives have been synthesized and characterized by spectroscopic methods. Their antitumor activities were evaluated against several classical prostate cancer cell lines including PC-3, LNCaP, and DU145. Among all the compounds, 9, 13, 17, 21 and 27 showed strong cytotoxic activities against DU145 cells (IC₅₀?<?1?μM). Further testing confirmed that compound 17 inhibited the growth of DU145 cells by inducing cell cycle arrest at G0/G1 phase. Besides, antagonistic activities of compounds (9, 13, 17, 21 and 27) towards a₁-ARs (α_1A, α_1B, and α_1D) were further evaluated using dual-luciferase reporter assays, and the compounds 13 and 17 exhibited better a₁-ARs subtype selectivity. The structure–activity relationship (SAR) of these developed arylpiperazine derivatives was rationally discussed. Taken together, these results suggested that further development of such compounds may be of great interest.