Synthesis and anticancer activity of dichloroplatinum(II) complexes of podophyllotoxin

A series of dichloroplatinum(II) complexes of podophyllotoxin (PPT) were prepared, and their cytotoxicity against sensitive (A-549, HeLa, HCT-8, Hep-G2, K562) and resistant (ADM/K562) cell lines were evaluated. Complex cis-[4α-O-(2″,3″-diaminopropanoyl)-podophyllotoxin] dichloride platinum(II) (12) displayed most potent cytotoxicity with IC₅₀ value in the range 0.071–2.98 μM. Complex 12 induces cell cycle arrest in the G₂/M phase, and inhibits the formation of microtubules in HeLa cells. Furthermore, this complex exhibits potent DNA cleavage capabilities.     

Pt(II) complexes with (N,N′) or (C,N,E)− (E = N,S) ligands: Cytotoxic studies,effect on DNA tertiary structure and structure–activity relationships

The cytotoxic activity of two series of platinum(II) complexes containing the polyfunctional imines R¹–CHN–R² [R¹ = phenyl or ferrocenyl unit and R² = (CH₂)_n–CH₂–NMe₂ where n = 1 or 2) (1 and 2) or C₆H₄-2-SMe (3)] acting as a bidentate (N,N′) (4–7) or terdentate [C(phenyl or ferrocenyl),N,N′]^? (8–10) or [C(ferrocenyl),N,S]^? ligand (11) in front of A549 lung, MDA-MB231 breast and HCT116 colon human adenocarcinoma cell lines is reported. The results reveal that most of the platinum(II) complexes are active against the three assayed lines and compounds 6, 7 and the platinacycles 10 and 11 exhibit a remarkable antiproliferative activity, even greater than cisplatin itself, in the cisplatin resistant HCT116 human cancer cell line. Electrophoretic DNA migration studies showed that most of them modify the DNA tertiary structure in a similar way as the reference cisplatin. Solution studies of a selection of the most relevant complexes have also been performed in order to test: (a) their stability in the aqueous biological medium and/or the formation of biologically active species and (b) their proclivity to react with 9-methylguanine (9-MeG), as a model nucleobase. Computational studies at DFT level have also been performed in order to explain the different solution behaviour of the complexes and their proclivity to react with the nucleobase.     

Two new glycosides and one new neolignan from the roots of Cynanchum stauntonii

Three new compounds including one C₂₁-steroidal glycoside, one methylglycoside, and one neolignan, named as Deoxyamplexicogenin A-3-O-yl-4-O-(4-O-α-l-cymaropyranosoyl-β-d-digitoxopyranosoyl)-β-d-canaropyranoside (1), Methyl-O-α-l-cymaropyranosoyl-(1 → 4)-β-D-digitoxopyranoside (2), and (+)-(7S, 8R, 7′E)-5-hydroxy-3, 5′-dimethoxy-4′, 7-epoxy-8, 3′-neolign-7′-ene-9, 9′-diol 9′-ethyl ether (3), respectively, were isolated from the roots of Cynanchum stauntonii. The structure elucidations were achieved by in-depth spectroscopic examination, mainly including the experiments and analyses of multiple 1D- and 2D-NMR and HRESIMS and CD analysis and qualitative chemical tests. Cytotoxicity activities of compounds 1–3 were evaluated against five tumor cell lines (HCT-8, Bel-7402, BGC-823, A549, and A2780) in cell based assays where they were found to be inactive.     

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.     

Synthesis and biological evaluation of 1,2,3-triazole linked aminocombretastatin conjugates as mitochondrial mediated apoptosis inducers

A series of 1,2,3-triazole linked aminocombretastatin conjugates were synthesized and evaluated for cytotoxicity, inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant anticancer activity against some representative human cancer cell lines and two of the conjugates 6d and 7c displayed potent cytotoxicity with IC₅₀ values of 53 nM and 44 nM against A549 human lung cancer respectively, and were comparable to combretastatin A-4 (CA-4). SAR studies revealed that 1-benzyl substituted triazole moiety with an amide linkage at 3-position of B-ring of the combretastatin subunit are more active compared to 2-position. G2/M cell cycle arrest was induced by these conjugates 6d and 7c and the tubulin polymerization assay (IC₅₀ of 1.16 μM and 0.95 μM for 6d and 7c, respectively) as well as immunofluorescence analysis showed that these conjugates effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Colchicine competitive binding assay suggested that these conjugates bind at the colchicine binding site of tubulin as also observed from the docking studies. Further, mitochondrial membrane potential, ROS generation, caspase-3 activation assay, Hoechst staining and DNA fragmentation analysis revealed that these conjugates induce cell death by apoptosis.     

Synthesis and biological evaluation of novel isoxazoles and triazoles linked 6-hydroxycoumarin as potent cytotoxic agents

A new series of diverse isoxazoles and triazoles linked 6-hydroxycoumarin (1) were synthesized using click chemistry approach. All the derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) cytotoxicity screening against a panel of five different human cancer cell lines viz. prostate (PC-3), colon (HCT-116 and Colo-205), leukemia (HL-60) and lung (A-549) to check their cytotoxic potential. Interestingly, among the tested molecules, some of the analogs displayed better cytotoxic activity than the parent 6-hydroxycoumarin (1). Of the synthesized isoxazoles, compounds 10 and 13 showed the best activity with IC₅₀ of 8.2 and 13.6 μM against PC-3 cancer cell line, while as, among the triazoles, compounds 23 and 25 were the most active with the IC₅₀ of 10.2 and 12.6 μM against A-549 cancer cell line. The other derivatives showed almost comparable activity with that of the parent molecule. The present study resulted in identification of ortho substituted isoxazole and triazole derivatives of 6-hydroxycoumarin as effective cytotoxic agents against prostate (PC-3) and lung (A-549) cancer cell lines, respectively.     

New antiproliferative 7-(4-(N-substituted carbamoylmethyl)piperazin-1-yl) derivatives of ciprofloxacin induce cell cycle arrest at G2/M phase

New N-4-piperazinyl derivatives of ciprofloxacin 2a–g were prepared and tested for their cytotoxic activity. The primary in vitro one dose anticancer assay experienced promising cytotoxic activity against different cancer cell lines especially non-small cell lung cancer. Independently, compounds 2b, 2d, 2f and 2g showed anticancer activity against human non-small cell lung cancer A549 cells (IC₅₀ = 14.8, 24.8, 23.6 and 20.7 μM, respectively) compared to the parent ciprofloxacin (IC₅₀ >100 μM) and doxorubicin as a positive control (IC₅₀ = 1 μM). The flow cytometric analysis for 2b showed dose dependent G₂/M arrest in A549 cells. Also, 2b increased the expression of p53 and p21 and decreased the expression of cyclin B1 and Cdc2 proteins in A549 cells without any effect on the same proteins expression in WI-38 cells. Specific inhibition of p53 by pifithrin-α reversed the G₂/M phase arrest induced by the 2b compound, suggesting contribution of p53 to increase. Taken together, 2b induced G₂/M phase arrest via p53/p21 dependent pathway. The results indicate that 2b can be used as a lead compound for further development of new derivatives against non-small cell lung cancer.     

Design,synthesis and biological evaluation of some novel benzothiazole/benzoxazole and/or benzimidazole derivatives incorporating a pyrazole scaffold as antiproliferative agents

In an aim at developing new antiproliferative agents, new series of benzothiazole/benzoxazole and/or benzimidazole substituted pyrazole derivatives 11a-c, 12a-c and 13a-c were prepared and evaluated for their antiproliferative activity against breast carcinoma (MCF-7) and non-small cell lung cancer (A549) cell lines. The target compound, 2-acetyl-4-[(3-(1H-benzimidazol-2-yl)-phenyl]-hydrazono-5-methyl-2,4-dihydropyrazol-3-one (12a) was the most active compound against both MCF-7 and A549 cell lines with half maximal inhibitory concentrations (IC₅₀) = 6.42 and 8.46 μM, respectively. Furthermore, the inhibitory activity of the all the target compounds against COX enzymes was recorded as a proposed mechanism for their antiproliferative activity. The obtained results revealed that the benzothiazolopyrazolone derivative 13c was the most potent COX-2 inhibitor (IC₅₀ = 0.10 μM), while the 5-acetylbenzimidazolylpyrazolone derivative 12a was the most COX-2 selective (S.I. = 104.67) in comparison with celecoxib (COX-2 IC₅₀ = 1.11 μM, S.I. = 13.33). Docking simulation on the most active compounds 12a and 13c had been performed to investigate the binding interaction of these active compounds within the binding site of COX-2 enzyme. Collectively, this work demonstrated the promising activity of the newly designed compounds as leads for further development into antiproliferative agents.     

Methanolysis of triterpenoid saponin from Ardisia gigantifolia stapf. and structure–activity relationship study against cancer cells

Thirteen 13,28-epoxy triterpenoid saponins were isolated from Ardisia gigantifolia stapf. and one potential anti-tumor saponin was methanolysised by H₂SO₄ to afford four new compounds. The seventeen compounds were evaluated for their anti-proliferative activity on A549, HCT-8 and Bel-7402 cells. The structure–activity relationship analysis indicated that the incorporation of O group at C-16, l-rhamnose at R⁵ and acetyl group at OH-6 of the d-glucose lead to a significant increase of the cytotoxic activity on A549 and HCT-8 but significant reduction of the cytotoxic activity on Bel-7402 cells. The synthesized saponins losing 13,28-epoxy and CHO at C-30, losed their cytotoxicities on A549 and HCT-8 cells, suggesting that the two moieties play an essential role for activity. 3β-O-α-l-rhamnopyranosyl-(1 → 3)-[β-d-xylopyranosyl-(1 → 2)]-β-d-glucopyranosyl-(1 → 4)-[β-d-glucopyranosyl-(1 → 2)]-α-l-arabinopyranoside-16α-hydroxy-13,28-epoxy-oleanane (2) showed better inhibitory activity to Bel-7402 (IC₅₀ 0.86 μM) than that of 5-FU (IC₅₀ 8.30 μM), which indicate that five saccharide and methyl moiety at C-30 are important for anti-proliferative activity. The activities of saponins 15 > 14, 17 > 16, suggested that the configuration of 28,30-epoxy is preferable to be 30(R) rather than 30(S) on Bel-7402 cells. Further molecular mechanism studies of saponins 1 and 2 were carried out on the cell cycle distribution of Bel-7402 cells.     

Lactarane sesquiterpenoids from Lactarius subvellereus and their cytotoxicity

Subvellerolactones B (1), D (2), and E (3), structurally unusual lactarane sesquiterpenoids, were isolated from the fruiting bodies of Lactarius subvellereus together with four known lactarane sesquiterpenes (4–7). The chemical structures and stereochemistries of compounds 1–3 were determined on the basis of spectroscopic analyses, including 1D and 2D NMR experiments and a convenient Mosher ester procedure. Subvellerolactone B (1) exhibited cytotoxicity against the A549, SK-MEL-2, and HCT-15 cell lines with IC₅₀ values of 26.5, 18.3, and 14.2 μM, respectively, and subvellerolactones D (2) and E (3) showed cytotoxicity against the A549 and HCT-15 cell lines (IC₅₀ (2): 25.1 and 17.8 μM, and IC₅₀ (3): 19.6 and 28.7 μM, respectively).     

Synthesis and antiproliferative activity of two diastereomeric lignan amides serving as dimeric caffeic acid-l-DOPA hybrids

Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl₃-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256 μM and periods of treatment of 24, 48 and 72 h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC₅₀ 64–70 μM) for the MDA-MB-231 cell line after 24–48 h of treatment, but they were more selective and much more potent (IC₅₀ 4–16 μM) for the MCF-7 cells after 48 h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72 h of treatment (IC₅₀ 1–2 μM), probably as the result of slow hydrolysis of their methyl ester functions.     

Synthesis and biological evaluation of platinum–acridine hybrid agents modified with bipyridine non-leaving groups

The use of 2,2′-bipyridines (4,4′-R₂-2,2′-bpy; R = H, Me, OMe, CF₃) as non-leaving groups (L–L) in platinum–acridinylthiourea conjugates, [PtCl(L-L)(ACRAMTU)](NO₃)₂, has been investigated. All bpy-substituted complexes (2–5) show micromolar activity in HL-60 (leukemia) and H460 (lung) cancer cell lines but proved to be significantly less potent than the prototypical compound (1) containing aliphatic ethane-1,2-diamine. NMR and mass spectrometry data indicate that bpy accelerates the reaction of platinum with DNA nitrogen, but the resulting adducts are more labile than those formed by the prototype.     

Synthesis and cytotoxicity evaluation of oleanolic acid derivatives

Twelve derivatives of oleanolic acid (1) have been synthesized and evaluated for their inhibitory activities against the growth of prostate PC3, breast MCF-7, lung A549, and gastric BGC-823 cancer cells by MTT assays. Within these series of derivatives, compound 17 exhibited the most potent cytotoxicity against PC3 cell line (IC₅₀ = 0.39 μM) and compound 28 displayed the best activity against A549 cell line (IC₅₀ = 0.22 μM). SAR analysis indicates that H-donor substitution at C-3 position of oleanolic acid may be advantageous for improvement of cytotoxicity against PC3, A549 and MCF-7 cell lines.     

Synthesis,and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (14a–e, 15a–g, 16a–e and 17a–g) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds (15e, 16a–b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC₅₀ values of 0.14 ± 0.08 μM, 0.24 ± 0.07 μM and 0.02 ± 0.01 μM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What’s more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity.     

Pseudo-disesquiterpenoids from seeds of Vernonia anthelmintica and their biological activities

Three new pseudo-disesquiterpenoids, vernodalidimer F – H (1 – 3), which are formed by esterification of two sesquiterpenoids, along with a new sesquiterpenoid (4) and two known sesquiterpeonids (5, 6) were isolated from the seeds of Vernonia anthelmintica. Their structures were elucidated by NMR data. The absolute configurations of 1–3 and 5 were determined by comparison of the experimental and calculated electronic circular dichroism spectra. Cytotoxicity of the isolated compounds against four human tumor cell lines were assayed. 5 exhibited strong cytotoxicity against HCT-15, PC-3, A549 and Hela cells lines with IC₅₀ values of 5.3, 5.6, 6.2, and 8.2 μM, respectively. 2 showed non-concentration dependent cytotoxicity against HCT-15, PC-3, and A549 cells lines with inhibition rate of 56.1%, 55.3%, and 50.1%, respectively. 1 and 3 showed moderate cytotoxicity against four cell lines with IC₅₀ values ranging from 12.2 ± 5.1 to 28.6 ± 2.5 μM. The influence of melanin content in B16 melanoma cells of 1, 5, and 6 were tested, and they increased melanin content by 43.6%, 28.1%, and 37.0% higher than positive control 8-methoxypsoralen.     

Synthesis of novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives via domino aldol-type/hetero Diels–Alder reaction and their cytotoxicity evaluation

New chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives have been synthesized by domino aldol-type reaction/hetero Diels–Alder reaction generated from o-quinone methide in situ from 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones with resorcinols/naphthols in the presence of 20 mol % ethylenediamine diacetate (EDDA), triethylamine (2 mL) as co-catalyst in CH₃CN under reflux conditions in good yields. The structures were established based on spectroscopic data, and further confirmed by X-ray diffraction analysis. The results showed that compounds 4h and 4j exhibited very potent cytotoxicity against human cervical cancer cell line (HeLa). Compound 4h displayed good inhibitory activity against both breast cancer cell lines, MDA-MB-231 and MCF-7. Further, the compound 4i exhibited good cytotoxicity against only MDA-MB-231, and compound 4j showed promising activity against human lung cancer cell line, A549 with IC₅₀ value of 2.53 ± 0.07 μM, which was comparable to the standard doxorubicin (IC₅₀ = 1.21 ± 0.1 μM).     

Synthesis of a terphenyl substituted 4-aza-2,3-didehydropodophyllotoxin analogues as inhibitors of tubulin polymerization and apoptosis inducers

A series of terphenyl based 4-aza-2,3-didehydropodophyllotoxin conjugates (8a–r) were synthesized by a straightforward one-step multicomponent synthesis that demonstrated anticancer activity against five human cancer cell lines (lung, colon, renal, prostate and cervical). All the tested compounds showed potent anticancer activity with IC₅₀ values ranging from 0.87 to 16.59 μM. Among them compounds 8n and 8p showed significant anticancer activity in lung cancer cells with IC₅₀ values 0.91 and 0.87 μM, respectively. Flow cytometric analysis revealed that these compounds induced cell cycle arrest in G₂/M phase in A549 cell line leading to caspase-3 dependent apoptotic cell death. The tubulin polymerization assay and immunofluorescence analysis showed that these compounds effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Further, Hoechst staining, DNA fragmentation analysis also suggested that these compounds induced cell death by apoptosis. Overall, the current study demonstrated that the synthesis of terphenyl based 4-aza-2,3-didehydropodophyllotoxin conjugates as promising anticancer agents with G₂/M cell cycle arrest and apoptotic-inducing activities via targeting tubulin.     

Pterocarpans and isoflavones from the root bark of Millettia micans and of Millettia dura

From the CH₂Cl₂/CH₃OH (1:1) extract of the root bark of Millettia micans, a new pterocarpan, (6aR,11aR)-3-hydroxy-7,8,9-trimethoxypterocarpan (1), named micanspterocarpan, was isolated. Similar investigation of the CH₂Cl₂/CH₃OH (1:1) extract of the root bark of Millettia dura gave a further new pterocarpan, (6aR,11aR)-8,9-methylenedioxy-3-prenyloxypterocarpan (2), named 3-O-prenylmaackiain, along with six known isoflavones (3-8) and a chalcone (9). All purified compounds were identified by NMR and MS, whereas the absolute configurations of the new pterocarpans were established by chriptical data analyses including quantum chemical ECD calculation. Among the isolated constituents, calopogonium isoflavone B (3) and isoerythrin A-4′-(3-methylbut-2-enyl) ether (4) showed marginal activities against the 3D7 and the Dd2 strains of Plasmodium falciparum (70–90% inhibition at 40 μM). Maximaisoflavone B (5) and 7,2′-dimethoxy-4′,5′-methylenedioxyisoflavone (7) were weakly cytotoxic (IC₅₀ 153.5 and 174.1 μM, respectively) against the MDA-MB-231 human breast cancer cell line. None of the tested compounds showed in-vitro translation inhibitory activity or toxicity against the HEK-293 human embryonic kidney cell line at 40 μM.     

Synthesis and anti-hepatitis C virus (HCV) activity of 3′-C-substituted-methyl pyrimidine and purine nucleosides

On the basis of potent anti-hepatitis C virus (HCV) activity of 2′-C-hydroxymethyladenosine, 3′-C-substituted-methyl-ribofuranosyl pyrimidine and purine nucleosides were designed and synthesized from d-xylose. Among compounds tested, all adenine analogues, 4a, 4d, and 4g showed significant anti-HCV activity in a replicon-based cell assay irrespective of the substituent (Y = OH, N₃, or F) at the 3′-C-substituted methyl position, among which 4g (Y = N₃) was the most potent, but it is also cytotoxic. This study guarantees the 3′-C-substituted-methyl nucleoside serves as a new template for the development of new anti-HCV agents.     

Synthesis and identification of α-cyano bis(indolyl)chalcones as novel anticancer agents

Microwave-assisted synthesis of 23 α-cyano bis(indolyl)chalcones (6a–w) and their in vitro anticancer activity against three human cancer cell lines have been discussed. Among the synthesized chalcones, compound 6n was found to be the most potent and selective against A549 lung cancer cell line (IC₅₀ = 0.8 μM). In a preliminary mechanism of action studies some α-cyano bis(indolyl)chalcones were found to enhance tubulin polymerization suggesting these compounds could act as microtubule stabilizing agents.