Design, synthesis and in vitro cytotoxicity of novel dinuclear platinum(II) complexes

Five dinuclear platinum(II) complexes with a novel chiral ligand, 2-(((1R,2R)-2-aminocyclohexylamino)methyl)phenol (HL), were designed, prepared and spectrally characterized. In vitro cytotoxicity of all the resulting platinum(II) compounds was evaluated against human HEPG-2, A549 and HCT-116 cell lines, respectively. Results indicated that all compounds showed positive biological activity. Particularly, compound D4 has lower IC₅₀ values than carboplatin toward HEPG-2 and A549, while compound D5 shows better activity than carboplatin against A549.     

Synthesis and cytotoxicity of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A

A series of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A were designed and synthesized in 7 steps. Most compounds exhibited comparable cytotoxicity against five human cancer cell lines (HCT-116, HepG2, BGC-823, A549 and A2780) to natural product ceratamine A. Compound 1k, bearing methoxy group at C-14, C-15 and C-16, showed the best in vitro cytotoxicity, which was better than ceratamine A. The structure and activity relationships study showed that the benzyloxymethyl group on N-3 played an important role on the cytotoxicity.     

Antitumor dinuclear platinum(II) complexes derived from a novel chiral ligand

A new chiral ligand, 2-(((1R,2R)-2-aminocyclohexyl)amino)acetic acid (HL), was designed and synthesized to prepare a series of novel dinuclear platinum(II) complexes with dicarboxylates or sulfate as bridges. The evaluation of these metal complexes in vitro cytotoxicity against human HCT-116, MCF-7 and HepG-2 cell lines were made. All compounds showed antitumor activity to HCT-116 and MCF-7. Particularly, compounds M3 and M5 not only exhibited better activity than carboplatin against MCF-7 and HepG-2, but also showed very close activity to oxaliplatin against HCT-116.     

On the stability and biological behavior of cyclometallated Pt(IV) complexes with halido and aryl ligands in the axial positions

A series of cyclometallated platinum(IV) compounds (3a, 3a′ and 3b′) with a meridional [C,N,N′] terdentate ligand, featuring an halido and an aryl group in the axial positions has been evaluated for electrochemical reduction and preliminary biological behavior against a panel of human adenocarcinoma (A-549 lung, HCT-116 colon, and MCF-7 breast) cell lines and the normal bronquial epithelial BEAS-2B cells. Cathodic reduction potentials (shifting from −1.463 to −1.570 V) reveal that the platinum(IV) compounds under study would be highly reluctant to be reduced in a biological environment. Actually ascorbic acid was not able to reduce complex 3a′, the most prone to be reduced according its reduction potential, over a period of one week. These results suggest an intrinsic activity for the investigated platinum(IV) complexes (3a, 3a′ and 3b′), which exhibit a remarkable cytotoxicity effectiveness (with IC₅₀ values in the low micromolar range), even greater than that of cisplatin. The IC₅₀ for A-549 lung cells and clog P values were found to follow the same trend: 3b′ > 3a′ > 3a. However, no correlation was observed between reduction potential and in vitro activity. As a representative example, cyclometallated platinum(IV) compound 3a′, exercise its antiproliferative activity directly over non-microcytic A-549 lung cancer cells through a mixture of cell cycle arrest (13% arrest at G1 phase and 46% arrest at G2 phase) and apoptosis induction (increase of early apoptosis by 30 times with regard to control). To gain further insights into the mode of action of the investigated platinum(IV) complexes, drug uptake, cathepsin B inhibition and ROS generation were also evaluated. Interestingly an increased ROS generation could be related with the antiproliferative activity of the cyclometallated platinum(IV) series under study in the cisplatin-resistant A-549 lung and HCT-116 cancer cell lines.     

Two new rotenoids from the roots of Millettia speciosa

Two new rotenoids, named millettiaosas A–B (1–2), together with four known compounds were isolated from the roots of Millettia speciosa. Their structures were elucidated on the basis of spectroscopic analysis including 1D and 2D NMR techniques and HRESIMS. Evaluation of the two new compounds for cytotoxicity against four human cancer cell lines (MCF-7, HCT-116, A549 and HepG-2) showed moderate activities (10 μM < IC₅₀ < 26 μM).     

Synthesis and characterisation of celastrol derivatives as potential anticancer agents

In the present study, three series of novel celastrol derivatives were designed and synthesised by modifying the carboxylic acid at the 20th position with amino acid, amine, and triazole derivatives. All the synthesised compounds were screened for their anticancer activities using MTT assay against AGS, MGC-803, SGC-7901, HCT-116, A549, HeLa, BEL-7402, and HepG-2 cell lines. Most of the synthesised compounds exhibited potent antiproliferative effects. The most promising compound 3-Hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic amide, N-(R)-methyl-3-(1H-indol-2-yl)propanoate (11) showed considerable high anticancer activity against AGS cell lines, with an IC₅₀ value of 0.44?μM, and considerably higher activities against HCT-116, BEL-7402, and HepG-2 cell lines, with IC₅₀ values of 0.78, 0.63, and 0.76?μM, respectively. The results of apoptosis tests and molecular docking study of compound 11 binding to Caspase-3 revealed that its mechanism of action with antiproliferative was possibly involved in inducing apoptosis by inducing the activation of caspase-3.     

Synthesis and biological evaluation of amino analogs of Ludartin: Potent and selective cytotoxic agents

Diverse amino analogs of Ludartin, a cytotoxic guaianolide and a position isomer of an anticancer drug, Arglabin were prepared through Michael type addition at its highly active α-methylene-γ-lactone motif. The semisynthetic derivatives were subjected to sulphorhodamine B cytotoxicity assay against a panel of four different human cancer cell lines viz. lung (A-549), leukemia (THP-1), prostate (PC-3) and colon (HCT-116) to look into structure–activity relationship. Few of the analogs displayed potent selective cytotoxicity compared to the parent molecule-Ludartin (1). (11R)-13-(Diethyl amine)-11,13-dihydroludartin (6) and (11R)-13-(piperidine)-11,13-dihydroludartin (10) showed almost same cytotoxicity against leukemia cell lines (THP-1) as that of parent molecule-Ludartin, but were more active against colon (HCT-116) cancer cells. (11R)-13-(Morpholine)-11,13-dihydroludartin (11) displayed selectively better cytotoxicity against Leukemia cancer cells (THP-1) exhibiting IC₅₀ of 2.8 μM. (11R)-13-(6-Nitroindazole)-11,13-dihydroludartin (17) was four times more potent than Ludartin with selective cytotoxic effects against prostate cancer cells (2.2 μM) while as (11R)-13-(6-nitroindazole)-11,13-dihydroludartin (18) exhibited three-fold selective cytotoxicity for Lung (A-549) cancer cell lines exhibiting IC₅₀ of 2.6 μM.     

Two new cytotoxic eudesmane sesquiterpenoids from Artemisia anomala

Two new eudesmane sesquiterpenoids artanoate (1) and eudesmanomolide (2) were isolated from the aerial parts of Artemisia anomala S. Moore. Their structures were elucidated as methyl (4R, 5S, 6S, 7S, 10R)-1-oxo-4, 6-dihydroxy-eudesma-2, 11 (13)-dien-12-oate (1) and (1R, 5R, 6R, 10R)-3, 13-diacetoxy-1-hydroxy-3, 7(11)-diene-12, 6-olide (2) on the basis of extensive spectroscopic analyses. Compound 1 showed cytotoxicity against HCT-8 cell lines with IC₅₀ value of 9.13 μM, and compound 2 exhibited inhibitory activities against HCT-8 and A549 cell lines with IC₅₀ values of 3.76 and 5.49 μM, respectively.     

Unveiling novel diphenyl-1H-pyrazole based acrylates tethered to 1,2,3-triazole as promising apoptosis inducing cytotoxic and anti-inflammatory agents

Meagre and suboptimal therapeutic response along with the side effect profile associated with the existing anticancer therapy have necessitated the development of new therapeutic modalities to curb this disease. Bearing in mind the current scenario, a series of 1,2,3-triazole linked 3-(1,3-diphenyl-1H-pyrazol-4-yl)acrylates was synthesized following a multi-step reaction scheme. Initial screening for anticancer potential was done by in vitro sulforhodamine B assay against four human cancer cell lines- MCF-7 (breast), A549 (Lung) and HCT-116 and HT-29 (Colon). On evaluation, several compounds showed promising growth inhibition against all the cell lines, particularly compounds 6e, 6f and 6n. Among them, compound 6f displayed IC₅₀ values of 1.962, 3.597, 1.764 and 4.496 µM against A549, HCT-116, MCF-7 and HT-29 cell lines respectively. Furthermore, the apoptosis inducing potential of the compounds was determined by Hoechst staining and DNA fragmentation assay. Colony formation inhibition assay was also carried out to determine the long term cytotoxic potential of the molecules. Moreover, compounds 6e, 6f and 6n were also evaluated for anti-inflammatory activity by protein albumin denaturation assay and red blood cell membrane stabilizing assay.     

Quinolidene based monocarbonyl curcumin analogues as promising antimycobacterial agents: Synthesis and molecular docking study

A series of quinoline incorporated monocarbonyl curcumin analogues was efficiently synthesized using [HDBU][HSO₄] as catalyst via Knoevenagel type condensation and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) and Mycobacterium bovis BCG in dormant state. The analogues 3e, 3h, 4a and 4e exhibited very good antitubercular activity. The antiproliferative activity of the analogues against MCF-7, A549 and HCT-116 cell lines was evaluated using modified MTT assay and these compounds were found to be non-cytotoxic. Molecular docking study has been carried out against M. tuberculosis pantothenate synthetase (MTB PS) enzyme in an effort to enhance the understanding of their action as antitubercular agents. The potency, low cytotoxicity and selectivity of these analogues support them as valid leads for further optimization.     

Synthesis and evaluation of the cell cycle arrest and CT DNA interaction properties of 4β-amino-4′-O-demethyl-4-deoxypodophyllotoxins

A series of 4β-amino-4′-O-demethyl-4-deoxypodophyllotoxin derivatives were synthesized, and their cytotoxicities against several human cancer cell lines, including HepG2, A549, HeLa and HCT-8 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4β-N-(4-Nitrophenyl piperazinyl)-4′-O-demethyl-4-deoxypodophyllotoxin (11) was found to be the most potent synthesized compound in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of cdc2, cyclin B1, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.     

Synthesis and antiproliferative evaluation of piperazine-1-carbothiohydrazide derivatives of indolin-2-one

By varying the substituents (R¹) at the indolin-2-one scaffold, a series of indolin-2-one derivatives bearing 4-phenylpiperazine-1-carbothiohydrazide moiety at the C3-position were synthesized and evaluated for their antiproliferative activity against three human cancer cell lines. We further selected the 5-chloroindolin-2-one moiety for the extension to another series of compounds by varying the substituents (R²) at the phenyl group connected with the piperazine ring. Among all the compounds synthesized, 6d and 6l were most potent with IC₅₀ values of 3.59 and 5.58 μM, respectively against A549 lung cancer cells, while 5f and 6l possessed IC₅₀ values of 3.49 and 4.57 μM, respectively against HCT-116 colon cancer cells which were comparable to that of Sunitinib, an indolin-2-one derivative in cancer therapy.     

Lignan glycosides from the Rhizomes of Smilax trinervula and their Biological activities

Phytochemical investigation of the rhizomes of Smilax trinervula led to isolation and structure elucidation of eight lignan glycosides, including five new lignans, namely, (7S, 8R, 8′R)-4, 4′, 9-trihydroxy-3, 3′, 5, 5′-tetramethoxy-7, 9′-epoxylignan-7′-one 4′-O-β-d-glucopyranoside (1), (7S, 8R, 8′R)-4, 4′, 9-trihydroxy-3, 3′, 5, 5′-tetramethoxy-7, 9′-epoxylignan-7′-one 4-O-β-d- glucopyranoside (2) (7S, 8R)-4, 9, 9′-trihydroxy-3, 3′, 5-trimethoxy-4′, 7-epoxy-8, 5′-neolignan 9′-O-β-d-glucopyranoside (3), (7R, 8R)-4, 9, 9′-trihydroxy-3, 5-dimethoxy-7.O.4′, 8.O.3′- neolignan 9′-O-β-d-glucopyranoside (4), and (7S, 8R)-4, 9, 9′-trihydroxy-3, 3′, 5-trimethoxy-8, 4′-oxy-neolignan 4-O-β-d-glucopyranoside (5), along with three known compounds (6-8). Their structures were established mainly on the basis of 1D and 2D NMR spectral data, ESI–MS and comparison with the literature. Compounds 1-8 were tested in vitro for their cytotoxic activity against four human tumor cell lines (SH-SY5Y, SGC-7901, HCT-116, Lovo). Compounds 3 and 5 exhibited cytotoxic activity against Lovo cells, with IC₅₀ value of 10.4 μM and 8.5 μM, respectively.     

Design,synthesis, molecular docking and biological activity evaluation of some novel indole derivatives as potent anticancer active agents and apoptosis inducers

Reaction of 5-morphilinosulfonylisatin (1) with acetophenones (2a–e) afforded 3-hydroxy-3-substituted-2-oxoindoles 3a-e, when treated with acetic acid the expected 3-phenacylidene-2-oxoindoles 4a-d and 4-hydroxy-5′-(morpholinosulfonyl) spiro [chromene-2, 3′-indolin]-2′-one 6 were obtained. Isatin derivative (1) was stirred with cyano derivatives to produce the arylidines (7a-c), while under reflux condition, it gave pyrrolo[2,3–b]indoles (8, 9). Moreover, istain (1) reacted with pyrazolo-5-one or 3-substituted phenol in presence of malononitrile to afford spiroxindole derivatives (10a,b) and (11a,b). Also, compounds (10a,b) and (11a,b) were obtained through cyclization of (7a) with pyrazolo-5-one or 3-substituted phenol. The obtained compounds were identified by IR, ¹H NMR, ¹³C NMR and elemental analysis. Anticancer activity against three cancer cell lines (HepG-2, HCT-116 and MCF-7) were evaluated using sulforhodamine B assay method. Compounds 4b, 4c, 7a, 7c and 9 showed broad spectrum anticancer activity on the three tested cell lines with IC₅₀ values less than 10 µM. Cell cycle analysis was performed for the most promising derivatives, compounds 4b and 7c arrested HepG-2 cells at G2-M phase, while compounds 7a and 9 accumulated cells at G0-G1 phase, all of them induced apoptosis at priG1 phase in the range of (11.32–19.17%). Additionally compounds 4b, 7a and 9 showed more potent activity against EGFR than Lapatinib, their IC₅₀ values are from 0.019 to 0.026 µM while IC₅₀ of Lapatinib is 0.028 µM. Molecular docking studies were conducted to investigate the binding mode, amino acid interactions and free binding energy of these potent derivatives.     

Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors

The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC₅₀ values of 6 and 3.5 µM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC₅₀ > 50 µM). It was demonstrated that compound 4a at 10 µM enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549.     

Green chemoselective synthesis of thiazolo[3,2-a]pyridine derivatives and evaluation of their antioxidant and cytotoxic activities

The green chemoselective synthesis of thiazolo[3,2-a]pyridine derivatives was achieved in water via microwave-assisted three-component reactions of malononitrile, aromatic aldehydes and 2-mercaptoacetic acid with molar ratios of 2:1:1.5 and 2:2.2:1, respectively. These compounds were subject to the experiments of antioxidant activity and cytotoxicity to carcinoma HCT-116 cells and mice lymphocytes. Nearly all of the tested compounds possessed potent capacities for scavenging free radicals. In addition, most of these compounds showed cytotoxicity to HCT-116 cells and mice lymphocytes with no selectivity. Of these, only thiazolo[3,2-a]pyridine derivative 5d suggested selective cytotoxicity to tumor cell line HCT-116 cells.     

Combination of 2-methoxy-3-phenylsulfonylaminobenzamide and 2-aminobenzothiazole to discover novel anticancer agents

The fragment of 2-substituted-3-sulfonylaminobenzamide has been proposed to replace the fragment of 2-substituted-3-sulfonylaminopyridine in PI3K and mTOR dual inhibitors to design novel anticancer agents based on bioisostere. The combination of the fragment of 2-substituted-3-sulfonylaminobenzamide with the fragment of 2-aminobenzothiazole or 2-aminothiazolo[5,4-b]pyridine, or 2-amino[1,2,4]triazolo[1,5-a]pyridine produced the novel structures of anticancer agents. As a result, nineteen target compounds were synthesized and characterized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines including HCT-116, A549, MCF-7 and U-87 MG. The SAR of target compounds was preliminarily discussed. Compound 1g with potent antiproliferative activity was examined for its effect on the AKT and p-AKT⁴⁷³. The anticancer effect of 1g was evaluated in established nude mice HCT-116 xenograft model. The results suggested that compound 1g can block PI3K/AKT/mTOR pathway and significantly inhibit tumor growth. These findings strongly support our assumption that the fragment of benzamide can replace the pyridine ring in some PI3K and mTOR dual inhibitor to design novel anticancer agents.     

Synthesis,biological evaluation,and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4–15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC₅₀ 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.     

Benzylisoquinoline alkaloids from the tubers of Corydalis ternata and their cytotoxicity

Chemical investigation of the tubers of Corydalis ternata resulted in the isolation and characterization of four new benzylisoquinoline alkaloids, epi-coryximine (1) and coryternatines A–C (2–4), along with 10 known alkaloids (5–14). Their structures were established on the basis of extensive spectroscopic data analyses and comparison with spectroscopic data reported. In addition, the cytotoxicities of the alkaloids (1–14) were evaluated by determining their inhibitory effects on several human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15) using the SRB assay. Compound 8 showed significant cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines (IC₅₀ = 8.34, 5.14, 7.87, and 2.86 μM, respectively). The four new compounds (1–4) exhibited selective cytotoxicity against the HCT-15 cell line.     

New Glycerolipids from the Traditional Chinese Medicine of Syngnathus acus (Hai-Long)

Two new glycerolipids, syngaculipids A and B ( 1 and 2 ), one first naturally occurring metabolite ( 8 ), together with five known compounds ( 3 – 7 ) were isolated from the AcOEt fraction of Syngnathus acus L. (Hai-Long). Their structures were elucidated by comprehensive spectral analyses involving UV, IR, MS, 1D and 2D NMR spectra and ECD calculations. All the isolated compounds were evaluated for their cytotoxicity against A549 and HCT-116 cell lines. Compound 8 exhibited moderate cytotoxicity with IC₅₀ values of 34.5 and 38.9 μM on the A549 and HCT-116 cell lines, respectively.