Synthesis and Cytotoxic Evaluation of Novel Thiazolocarbazoles. Part II1

Novel thiazolocarbazole derivatives have been synthesized via the corresponding imino-1,2,3-dithiazoles. In vitro antitumor activity of these polyheterocyclic compounds was studied.     

Microwave-assisted Synthesis of Novel Thiazolocarbazoles and Evaluation as Potential Anticancer Agents. Part III

Novel 6-substituted thiazolocarbazole derivatives have been synthesized under microwave irradiation via the corresponding imino-1,2,3-dithiazoles. In vitro antitumor potential of these polyheterocyclic compounds was evaluated. Among all the tested thiazolocarbazoles, compound 10 is the most effective in inhibiting cell growth.     

Synthesis and Cytotoxic Activity of Thiazolofluorenone Derivatives

The synthesis and biological evaluation of some novel thiazolofluorenones, thiazolofluorenes and thiazoloanthraquinones, substituted with amino side-chains are described. These polyheterocyclic compounds have been synthesized via the corresponding imino-1,2,3-dithiazoles. Their cytotoxic activity and their eventual selective effect on a phase of the cell cycle were evaluated in vitro, using the murine lymphocytic L1210 leukaemia cell line.     

Synthesis and biological evaluation of bergenin-1,2,3-triazole hybrids as novel class of anti-mitotic agents

In continuation of our investigation of pharmacologically-motivated natural products, we have isolated bergenin (1) as a major compound from Mallotus philippensis, which is deployed in different Indian traditional systems of medicine. Here, a series of bergenin-1,2,3-triazole hybrids were synthesized and evaluated for their potentials against a panel of cancer cell lines. Several of the hybrid derivatives were found more potent in comparison to parent compound bergenin (1). Among them, 4j demonstrated potent activity against A-549 and HeLa cell lines with IC₅₀ values of 1.86 µM and 1.33 μM, respectively, and was equipotent to doxorubicin. Cell cycle analysis showed that 4j arrested HeLa cells at G2/M phase and lead to accumulation of Cyclin B1 protein. Cell based tubulin polymerization assays and docking studies demonstrated that 4j disrupts tubulin assembly by occupying colchicine binding pocket of tubulin.     

Synthesis of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives and their cytotoxic activity

A series of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives 3 and 4 were prepared respectively starting from 6-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine 1 via selective N-propargylation, followed by reaction with diverse substituted alkyl/perfluoroalkyl/aryl/aryl amide azides under Sharpless conditions. All the synthesized compounds 3 and 4 were screened for cytotoxic activity against four human cancer cell lines such as U937, THP-1, HL60 and B16-F10. Compounds 3e, 4g, 4i and 4j which showed promising activity have been identified.     

Synthesis of Coumarin Derivatives with Cytotoxic,Antibacterial and Antifungal Activity

The synthesis and selective biological screening of 7-hydroxy-4-methyl-2H-chromen-2-one (2), 7-hydroxy-4,5-dimethyl-2H-chromen-2-one (15) and some of their derivatives were carried out. Compound 13 was found to be most potent cytotoxic agent with LD₅₀ = 126.69 μg/ml. In antibacterial assay the compounds showed a broad spectrum of activities. Compound 11 exhibited a very high degree of plant growth inhibition at three levels of concentration. Compound 4 showed very promising antifungal activity against Candida albicans. Compounds 12 and 13 demonstrated excellent antioxidant activity.     

Synthetic Chalcone Derivatives as Inhibitors of Cathepsins K and B,and Their Cytotoxic Evaluation

A series of chalcone derivatives, 1 – 15 , were prepared by Claisen? Schmidt condensation and evaluated for their cytotoxicities on tumor cell lines and also against proteolytic enzymes such as cathepsins B and K. Of the compounds synthesized, (E)‐3‐(3,4‐dimethoxyphenyl)‐1‐phenylprop‐2‐en‐1‐one ( 12 ), (E)‐3‐(4‐chlorophenyl)‐1‐phenylprop‐2‐en‐1‐one ( 13 ), (E)‐3‐(4‐methoxyphenyl)‐1‐phenylprop‐2‐en‐1‐one ( 14 ), and (E)‐3‐(4‐nitrophenyl)‐1‐phenylprop‐2‐en‐1‐one ( 15 ) showed significant cytotoxicities. The most effective compound was 15 , which showed high cytotoxic activity with an IC₅₀ value lower than 1 μg/ml, and no selectivity on the tumor cells evaluated. Substituents at C(4) of ring B were found to be essential for cytotoxicity. In addition, it was also demonstrated that some of these chalcones are moderate inhibitors of cathepsin K and have no activity against cathepsin B.     

Synthesis and anti-proliferative activity of allogibberic acid derivatives containing 1,2,3-triazole pharmacophore

Sixty novel allogibberic acid derivatives containing 1,2,3-triazole pharmacophore were designed and synthesized. The key chemical processes include aromatization of the A ring in gibberellins, formation of allogibberic azides and its copper mediated Huisgen 1,3-dipolar cycloaddition with alkynes. A number of hybrids containing α,β-unsaturated ketone moiety exhibited excellent in vitro cytotoxic activities. Some of the hybrids were more selective to MCF-7 and SW480 cell lines with IC₅₀ values at least 8-fold more cytotoxic than cisplatin (DDP). The most potent compounds C43 and C45 are more cytotoxic than cisplatin (DDP) against all tested five tumor cell lines, with IC₅₀ values of 0.25–1.72?µM. Mechanism of action studies indicated that allogibberic-triazole derivative C45 could induce the S phase cell cycle arrest and apoptosis in SMMC-7721 cell lines.     

1,5-Disubstituted 1,2,3-triazoles as cis-restricted analogues of combretastatin A-4: Synthesis, molecular modeling and evaluation as cytotoxic agents and inhibitors of tubulin

A series of cis-restricted 1,5-disubstituted 1,2,3-triazole analogues of combretastatin A-4 (1) have been prepared. The triazole 12f, 2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline, displayed potent cytotoxic activity against several cancer cell lines with IC₅₀ values in the nanomolar range. The ability of triazoles to inhibit tubulin polymerization has been evaluated, and 12f inhibited tubulin polymerization with IC₅₀ = 4.8 μM. Molecular modeling experiments involving 12f and the colchicine binding site of ,β-tubulin showed that the triazole moiety interacts with β-tubulin via hydrogen bonding with several amino acids.     

Synthesis and Biological Evaluation of Matijin‐Su Derivatives as Potential Antihepatitis B Virus and Anticancer Agents

A series of Matijin‐Su (MTS, (2S)‐2‐{[(2S)‐2‐benzamido‐3‐phenylpropanoyl]amino}‐3‐phenylpropyl acetate) derivatives were synthesized and evaluated for their anti‐HBV and cytotoxic activities in vitro. Six compounds ( 4g , 4j , 5c , 5g , 5h and 5i ) showed significant inhibition against HBV DNA replication with the IC₅₀ values in range of 2.18 – 8.55 μm , which were much lower than that of positive control lamivudine (IC₅₀ 82.42 μm ). In particular, compounds 5h (IC₅₀ 2.18 μm ; SI 151.59) and 5j (IC₅₀ 5.65 μm ; SI 51.16) displayed relatively low cytotoxicities, resulting in high SI values. Notably, besides the anti‐HBV DNA replication activity, compound 4j also exhibited more potent in vitro cytotoxic activity than 5‐fluorouracil in two hepatocellular carcinoma cell (HCC) lines (QGY‐7701 and SMMC‐7721), indicating that 4j may be a promising lead for the exploration of drugs with dual therapeutic effects on HBV infection and HBV‐induced HCC.     

Biologically Active Heterocyclic Hybrids Based on Quinazolinone,Benzofuran and Imidazolium Moieties: Synthesis,Characterization, Cytotoxic and Antibacterial Evaluation

Cytotoxic and antimicrobial agents structurally based on quinazolinone, benzofuran and imidazole pharmacophores, have been designed and synthesized. Spectral (IR, ¹H‐NMR) and elemental analysis data established the structures of these novel 3‐[1‐(1‐benzofuran‐2‐yl)‐2‐(4‐oxoquinazolin‐3(4H)‐yl)ethyl]‐1‐methyl‐1H‐imidazol‐3‐ium chloride hybrid derivatives. All the synthesized compounds were evaluated for in vitro cytotoxicity and antimicrobial activities. Cytotoxic evaluation using MTT assay revealed that compounds 12c , 12g and 12i exhibited significant cytotoxicity with IC₅₀ values 1, 1, and 0.57 μm on this cell line, respectively. Biological activity of the synthesized compounds as antibacterial agent were also evaluated against three Gram‐negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi), three Gram‐positive (Staphylococcus aureus, Bacillus subtilis and Listeria monocitogenes) and one yeast‐like fungi (Candida albicans) strains. All compounds 12a  –  12i showed slightly higher activity against Gram‐positive bacteria than the Gram‐negative one. Among the nine new compounds screened, 3‐[1‐(5‐bromo‐1‐benzofuran‐2‐yl)‐2‐(6‐chloro‐4‐oxoquinazolin‐3(4H)‐yl)ethyl]‐1‐methyl‐1H‐imidazol‐3‐ium chloride ( 12e ) has pronounced higher antimicrobial activity against all tested strains. These results demonstrated potential importance of molecular hybridization in the development of new lead molecules with major cytotoxicity and antimicrobial activity.     

Synthesis,Characterization and Evaluation of Cytotoxic Activities of Novel Aziridinyl Phosphonic Acid Derivatives

New aziridine 2‐phosphonic acids were prepared by monohydrolysis of the aziridine 2‐phosphonates that were obtained by the modified Gabriel?Cromwell reaction of vinyl phosphonate or α‐tosylvinyl phosphonate with a primary amine or a chiral amine. The cellular cytotoxicity of these compounds was tested against the HCT‐116 colorectal cancer cell lines and the CCD‐18Co normal colon fibroblast lines using the MTT assay. Three of the synthesized phosphonic acid derivatives 2e (ethyl hydrogen {(2S)‐1‐[(1S)‐1‐(naphthalen‐2‐yl)ethyl]aziridin‐2‐yl}phosphonate), 2h (ethyl hydrogen (1‐benzylaziridin‐2‐yl)phosphonate), and 2i (ethyl hydrogen (1‐cyclohexylaziridin‐2‐yl)phosphonate) showed higher cytotoxicity than the reference cancer treatment agent etoposide. Cell death was through a robust induction of apoptosis even more effectively than etoposide, a well‐known apoptosis inducing agent.     

Synthesis and antitumor evaluation of benzopsoralen analogues

The synthesis of five new tetracyclic benzopsoralen analogues, compounds 2-6, with 9H-xanthen-9-one or 9H-carbazole frameworks, is described. Their inhibitory effects on the growth of three human tumor cell lines (MCF-7, SF-268, and NCI-460) were evaluated, and discussed in terms of structure-activity relationship, taking into account both geometric and electronic features. Generally, the angular compounds showed significant biological activities, but the arrangement of functional groups also contributed to the overall activity.     

Novel Nucleoside Analogues: First Synthesis of Pyridine-4-Thioglycosides and Their Cytotoxic Evaluation

The reaction of sodium 2,2-dicyanoethene-1,1-bis(thiolate) with 2-cyano-N-arylacetamides afforded sodium pyridine-4-thiolates, coupling of the latters with 2,3,4,6-tetra-O-acetyl-D-gluco- and D-galactopyranosyl bromides, respectively, afforded new pyridine-4-thioglycosides. Ammonolysis of the latter compounds afforded the free thioglycosides. The antitumor activities of the synthesized compounds were tested against human tumor cell lines; lung (A549), colon (HCT116), liver (HEPG2), and prostate (PC3).     

Synthesis and biological evaluation of nimesulide based new class of triazole derivatives as potential PDE4B inhibitors against cancer cells

A new class of 1,2,3-triazol derivatives derived from nimesulide was designed as potential inhibitors of PDE4B. Synthesis of these compounds was carried out via a multi-step sequence consisting of copper-catalyzed azide–alkyne cycloaddition (CuAAC) as a key step in aqueous media. The required azide was prepared via the reaction of aryl amine (obtained from nimesulide) with α-chloroacetyl chloride followed by displacing the α-chloro group by an azide. Some of the synthesized compounds showed encouraging PDE4B inhibitory properties in vitro that is >50% inhibition at 30 μM that were supported by the docking studies of these compounds at the active site of PDE4B enzyme (dock scores ～ ?28.6 for a representative compound). Two of these PDE4 inhibitors showed promising cytotoxic properties against HCT-15 human colon cancer cells in vitro with IC₅₀ ～ 21–22 μg/mL.     

Phytochemical Investigation and Cytotoxic Evaluation of the Components of the Medicinal Plant Ligularia atroviolacea

A phytochemical investigation of the roots of Ligularia atroviolacea resulted in the isolation of 24 compounds including seven new eremophilanoids named eremophila‐3,7(11),8‐triene‐12,8;14,6α‐diolide ( 1 ), 3β‐(angeloyloxy)eremophil‐7(11)‐en‐12,8β‐olid‐14‐oic acid ( 2 ), 1α‐chloro‐10β‐hydroxy‐6β‐(2‐methylpropanoyloxy)‐9‐oxo‐7,8‐furoeremophilane ( 3 ), (10βH)‐8‐oxoeremophila‐3(4),6(7)‐diene‐12,14‐dioic acid ( 4 ), (10αH)‐8‐oxoeremophila‐3(4),6(7)‐diene‐12,14‐dioic acid ( 5 ), 8β‐[eremophila‐3′,7′(11′)‐diene‐12′,8′α;14′,6′α‐diolide]eremophila‐3,7(11)‐diene‐12,8α;14,6α‐diolide ( 6 ), and ligulatrovine A ( 7 ), eleven known eremophilanoids, 8 – 18 , four steroids, one glucose derivative, and one fatty acid. The structures of these compounds were elucidated by spectroscopic methods including 2D‐NMR experiments. The structure of 3 was also established by an X‐ray diffraction study. The in vitro cytotoxicity evaluation of selected compounds was performed on seven cultured tumor cell lines, i.e., KB, BEL‐7404, A549, HL‐60, HeLa, CNE, and P‐388D1. The preliminary taxonomy of this species was also discussed, and the possible biogenesis of a dimer possessing a new noreremophilanoid type skeleton, 7 , is presented in a preliminary form.     

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.     

Design and Synthesis of Novel Cytotoxic Indole‐Thiosemicarbazone Derivatives: Biological Evaluation and Docking Study

In this work, two novel series of indole‐thiosemicarbazone derivatives were designed, synthesized, and evaluated for their cytotoxic activity against MCF‐7, A‐549, and Hep‐G2 cell lines in comparison to etoposide and colchicine as the reference drugs. Generally, the synthesized compounds showed better cytotoxicity towards A‐549 and Hep‐G2 than MCF‐7. Among them, (2E)‐2‐{[2‐(4‐chlorophenyl)‐1H‐indol‐3‐yl]methylidene}‐N‐(4‐methoxyphenyl)hydrazinecarbothioamide ( 8l ) was found to be the most potent compound against A‐549 and Hep‐G2, at least three times more potent than etoposide. The morphological analysis by the acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that compound 8l induced apoptosis in A‐549 cells. Moreover, molecular docking methodology was exploited to elucidate the details of molecular interactions of the studied compounds with putative targets.     

Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolinyl substituted 1,2,3-triazole derivatives: Their evaluation as potential PDE 4B inhibitors possessing cytotoxic properties against cancer cells

The 2,2,4-trimethyl-1,2-dihydroquinolinyl substituted 1,2,3-triazole derivatives were designed as potential inhibitors of PDE4B. These compounds were synthesized via a multi-step sequence consisting of copper-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step in aqueous media. The required alkynes were prepared from nimesulide via N-propargylation and then nitro group reduction followed by a CAN mediated modified Skraup reaction of the resulting amine. All the synthesized compounds showed PDE4B inhibitory properties in vitro at 30 μM with two compounds showing >50% inhibition that were supported by the in silico docking results of these compounds at the active site of PDE4B. Three of these PDE4 inhibitors showed promising cytotoxic properties against A549 human lung cancer cells in vitro with IC₅₀ ∼8–9 μM.