Chloro acridone derivatives as cytotoxic agents active on multidrug-resistant cell lines and their duplex DNA complex studies by electrospray ionization mass spectrometry

We report herein in vitro anti-proliferative activity and duplex DNA complex studies of a series of N10-substituted acridone derivatives. All the molecules have been designed on the basis of the presence of specific recognition patterns consisting of hydrogen bond acceptors (or electron donors), carbonyl, chloro groups with precise spatial separation and structural features (lipophilicity, positive charge at neutral pH and presence of aromatic rings). The in vitro cytotoxic effects have been demonstrated against human promyelocytic leukemia sensitive cell line (HL-60), including its multidrug cross-resistance of two main (P-gp and MRP) phenotype sublines vincristine-resistant (HL-60/VINC) and doxorubicin-resistant (HL-60/DX) cancer cell lines. Compound 4 showed very good activity against sensitive and resistant cell lines. The noncovalent complexes of these molecules with DNA duplex has been investigated in gas phase by using a fast, robust and sensitive electrospray ionization mass spectrometry (ESI-MS) technique. Equilibrium association constants (K1) and percentage of intact complexes were determined. The combined results show that these acridone derivatives interact with DNA duplex by intercalation between the base pairs, possess higher affinity to GC than AT base pairs of the DNA and they could not interact noncovalently with the minor grooves of the DNA in solution-free gas phase. Examination of the relationship between lipophilicity and cytotoxic properties of acridone derivatives showed a poor correlation. The in vitro cytotoxic studies in resistant cancer cell lines of compound 4 showed that it might be a promising new hit for further development of anti-MDR agent.     

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.     

Synthesis and anticancer activity of quinopimaric and maleopimaric acids’ derivatives

A series of quinopimaric and maleopimaric acids’ derivatives modified in the E-ring, at the carbonyl- and carboxyl-groups were synthesized and their in vitro cytotoxic activity was evaluated at the National Cancer Institute, USA. Methyl esters of dihydroquinopimaric, 1a,4a-dehydroquinopimaric, 2,3-epoxyquinopimaric, 1-ethylenketal-dihydroquinopimaric, 1-ethylenketal-4-hydroxyiminodihydroquinopimaric acids displayed an activity on renal cancer, leukemia, colon cancer and breast cancer cell lines in concentration 10⁻⁵ M. Methyl 1,4-dihydroxyiminodihydroquinopimarate showed both a potent and broad spectrum of cytotoxic activity against NSC lung cancer, colon cancer, breast cancer, renal cancer and leukemia and revealed in vivo antineoplastic activity towards mouse solid transplantable mammary carcinoma Ca755 and colon adenocarcinoma AKATOL. The information about antineoplastic activity of the studied quinopimaric and maleopimaric acids’ derivatives will be used for hit to lead optimization in these chemical series.     

Design,Synthesis and Anticancer Evaluation of New Substituted Thiophene-Quinoline Derivatives

A series of new isoxazolyl, triazolyl and phenyl based 3-thiophen-2-yl-quinoline derivatives were synthesized adopting click chemistry approach. In addition, the synthesis of new useful synthon, (2-chloroquinolin-3-yl) (thiophen-2-yl) methanol, is reported. The obtained compounds were characterized by spectral data analysis and evaluated for their anticancer activity. All the derivatives were subjected to in vitro MTT cytotoxicity screening assay against a panel of four different human cancer cell lines, liver (HepG-2), colon (HCT-116), human cervical cancer (HeLa) and breast (MCF-7). Out of a library of 17 compounds, two compounds have been identified as potent and selective cytotoxic agents against HeLa and MCF-7 cell lines. SAR studies for such hybridized analogues were investigated and phenyl derivatives were proved to be more potent than isoxazole and triazole derivatives. Furthermore, the promising compounds were selected for in vitro inhibition of EGFR-TK and Topo II enzymes. Also, they were subjected to cell cycle arrest analysis and apoptosis assay on MCF-7 cells. Our recent finding highlights these thiophene-quinoline analogues as a promising class of compounds for further studies concerning new anticancer therapies.     

Design and synthesis of harzialactone analogues: promising anticancer agents

New homologues of harzialactone were synthesized using D-glucose as chiral template. Wittig reaction to introduce aromatic moiety in 10 and chemoselective anomeric oxidation of 13 were used as key reactions in our synthesis. Anticancer activity of these target molecules was assessed against five cancer cell lines, P388D1, HL60, COLO-205, Zr-75-1 and HeLa. Both compound 5 and 6, showed significant activity against colon cancer (COLO-205) and cervical cancer (HeLa) and moderate with others. To the best of our knowledge, this is the first report of harzialactone analogues as potent inhibitors of human colon and cervical cancer.     

Synthesis of carbazoloquinone derivatives and their antileukemic activity via modulating cellular reactive oxygen species

Carbazoloquinone alkaloids are of great interest as privileged structures for anticancer drug molecules. The purpose of this study was to investigate the structure-activity relationships of carbazoloquinone derivatives as anticancer agents. A series of carbazoloquinones including murrayaquinone A, koeniginequinones A and B, and related analogues were therefore prepared. Palladium-catalyzed intramolecular cyclization reaction mechanism was well elucidated by DFT calculations. Treatment of the synthesized derivatives showed cytotoxicity on human leukemia HL-60 cells in a dose-dependent fashion. In addition, murrayaquinone A and β-brazanquinone elevated cellular levels of reactive oxygen species (ROS), thereby triggering apoptosis. Our findings emphasize the excellent potential of carbazoloquinone derivatives as ROS-inducing anticancer agents.     

Synthesis of a new class of 2-anilino substituted nicotinyl arylsulfonylhydrazides as potential anticancer and antibacterial agents

A series of N'-1-[2-anilino-3-pyridyl]carbonyl-1-benzenesulfonohydrazide derivatives (7a-i) was synthesized and five of them were selected by the National Cancer Institute (NCI) and evaluated for their in vitro anticancer activity. Three of the investigated compounds 7d, 7f and 7g exhibited significant anticancer activity in the primary assay and further tested against a panel of 60 human tumour cell lines. Compound 7g showed 50% growth inhibitory activity in leukaemia, melanoma, lung cancer, colon cancer, renal cancer and breast cancer cells with GI(50) value of 3.2-9.6 microM. The synthesized compounds (7a-i) were also evaluated for their antibacterial activity against various Gram-positive and Gram-negative strains of bacteria. Most of these compounds showed better inhibitory activity in comparison to the standard drugs.     

Synthesis and antitumor activity of cholest-4 alpha-methyl-7-en-3beta-ol derivatives

Cholest-4 alpha-methyl-7-en-3beta-ol (1) has potent inhibitory activity against pc 12 tumor with 0.5043 ratio (10 microg/mL). This paper describes a series of structural modification of this compound, which focus on 3beta-hydroxyl group and 7(8)-double bond. The synthesized derivatives of 1 were tested for human cancer cell lines including colon cancer (HCT-8), liver cancer (BEL-7402) and nasopharyngeal cancer (KB) cells. The results showed that cholest-4 alpha-methyl-8-en-3beta,7 alpha-diol 6a inhibits KB cell significantly with IC(50) 1.32 x 10(-9)microg/mL. In addition, the cytotoxic properties of this compound against HCT-8 and BEL-7402 are excellent with IC(50) 1.2 microg/mL.     

The 5-hydrazino-3-methylisothiazole-4-carboxylic acid,its new 5-substituted derivatives and their antiproliferative activity

Currently, the basic method of treatment of colon cancer is surgery. The range of anticancer drugs used in the treatment of colorectal cancer is small and is based mainly on systemic combination chemotherapy. As a result of the designed syntheses, we received new isothiazole derivatives with anticancer activity. The synthesized 5-hydrazino-3-methylisothiazole-4-carboxylic acid has never been obtained before. It is also a substrate for the synthesis of its innovative derivatives, i.e. compounds that are Schiff bases. The identification of the structure of new compounds was carried out using mass spectrometry (MS), proton nuclear magnetic resonance spectroscopy (¹H NMR), carbon nuclear magnetic resonance spectroscopy (¹³C NMR) and infrared spectroscopy (IR). Potential antitumor activity was confirmed in antiproliferative MTT and SRB tests. The selected, most biologically active substances were characterized by high selectivity towards leukemia and colon cancer cell lines. They caused high inhibition of proliferation of human biphenotypic B cell myelomonocytic leukemia MV4-11 (13 compounds), human colon adenocarcinoma cell lines sensitive LoVo (8 compounds) and resistant to doxorubicin LoVo/DX (12 compounds). However, in the conducted studies, their activity against breast adenocarcinoma MCF-7 and normal non-tumorigenic epithelial cell line derived from mammary gland MCF-10A was substantially lower. The result of this work is claimed Polish patent application.     

Design and synthesis of Hsp90 inhibitors: Exploring the SAR of Sansalvamide A derivatives

Utilizing the structure–activity relationship we have developed during the synthesis of the first two generations and mechanism of action studies that point to the interaction of these molecules with the key oncogenic protein Hsp90, we report here the design of 32 new Sansalvamide A derivatives and their synthesis. Our new structures, designed from previously reported potent compounds, were tested for cytotoxicity on the HCT116 colon cancer cell line, and their binding to the biological target was analyzed using computational studies involving blind docking of derivatives using Autodock. Further, we show new evidence that our molecules bind directly to Hsp90 and modulate Hsp90’s binding with client proteins. Finally, we demonstrate that we have integrated good ADME properties into a new derivative.     

Syndecan-2 mediates adhesion and proliferation of colon carcinoma cells

Syndecan-2 is a transmembrane heparan sulfate proteoglycan whose function at the cell surface is unclear. In this study, we examined the function of syndecan-2 in colon cancer cell lines. In several colon cancer cell lines, syndecan-2 was highly expressed compared with normal cell lines. In contrast, syndecan-1 and -4 were decreased. Cell biological studies using the extracellular domain of recombinant syndecan-2 (2E) or spreading assay with syndecan-2 antibody-coated plates showed that syndecan-2 mediated adhesion and cytoskeletal organization of colon cancer cells. This interaction was critical for the proliferation of colon carcinoma cells. Blocking with 2E or antisense syndecan-2 cDNA induced G(0)/G(1) cell cycle arrest with concomitantly increased expression of p21, p27, and p53. Furthermore, blocking of syndecan-2 through antisense syndecan-2 cDNA significantly reduced tumorigenic activity in colon carcinoma cells. Therefore, increased syndecan-2 expression appears to be a critical for colon carcinoma cell behavior, and syndecan-2 regulates tumorigenic activity through regulation of adhesion and proliferation in colon carcinoma cells.     

Synthesis and in vitro antiproliferative activities of (5-aryl-1,2,4-oxadiazole-3-yl) methyl d-ribofuranosides

The emergence of multidrug resistance cell lines is one of the major obstacles in the success of cancer chemotherapeutic treatment. Therefore, it remains a big challenge the development of new and effective drugs to defeat cancer. The presence of nitrogen heterocycles in the architectural design of drugs has led to the discovery of new leading compounds. Herein, we report the synthesis, characterization and in vitro antiproliferative activity against six cancer cell lines of d-ribofuranoside derivatives bearing a 1,2,4-oxadiazolic ring, with the aim of developing new active compounds. Most of these derivatives exhibit significant antiproliferative activities in the micromolar range. Noteworthy, the most potent compound of the series showed better selectivity towards the more resistant colon cancer cell line WiDr.     

Synthesis of chalcone derivatives on steroidal framework and their anticancer activities

Chalcone derivatives on estradiol framework have been synthesized. Some of the derivatives showed potent anticancer activity against some human cancer cell lines. Compounds 9 and 19 showed potent activity against MCF-7, a hormone dependent breast cancer cell line. Chalcone 7 was further modified to the corresponding indanone derivative (19) using the Nazarov reaction, which showed better activity than the parent compound against the MCF-7 breast cancer cell line. Active anticancer derivatives were also evaluated for osmotic hemolysis using the erythrocyte as a model system. It was observed that chalcone derivatives showing cytotoxicity against cancer cell lines did not affect the fragility of erythrocytes and hence may be considered as non-toxic to normal cells.     

Synthesis of taxoids 5. Synthesis and evaluation of novel water-soluble prodrugs of a 3'-desphenyl-3'-cyclopropyl analogue of docetaxel.

A novel 3'-desphenyl-3'-cyclopropyl analogue of docetaxel was synthesized from 10-deacetyl-baccatin III. The cytotoxicity of the new taxoid was evaluated against several human tumor cell lines, and it had ca. 20 times stronger activity against human colon cancer cell lines (WiDr and Colon 320) than that of docetaxel. This taxoid was converted to its water-soluble prodrugs that have 2'-substituted amino acid derivatives with spacer. The prodrugs had good solubility in saline and showed more potent antitumor activity against B 16 melanoma in mice than that of docetaxel.     

Synthesis and biological evaluation of pyrazole linked benzothiazole-β-naphthol derivatives as topoisomerase I inhibitors with DNA binding ability

A series of new pyrazole linked benzothiazole-β-naphthol derivatives were designed and synthesized using a simple, efficient and ecofriendly route under catalyst-free conditions in good to excellent yields. These derivatives were evaluated for their cytotoxicity on selected human cancer cell lines. Among those, the derivatives 4j, 4k and 4l exhibited considerable cytotoxicity with IC₅₀ values ranging between 4.63 and 5.54?µM against human cervical cancer cells (HeLa). Structure activity relationship was elucidated by varying different substituents on benzothiazoles and pyrazoles. Further, flow cytometric analysis revealed that these derivatives induced cell cycle arrest in G2/M phase and spectroscopic studies such as UV–visible, fluorescence and circular dichroism studies showed that these derivatives exhibited good DNA binding affinity. Additionally, these derivatives can effectively inhibit the topoisomerase I activity. Viscosity studies and molecular docking studies demonstrated that the derivatives bind with the minor groove of the DNA.     

Antiproliferative activity of novel thiopyran analogs on MCF-7 breast and HCT-15 colon cancer cells: synthesis, cytotoxicity, cell cycle analysis, and DNA-binding

A series of 6H-thiopyran-2,3-dicarboxylate derivatives 4a-d were synthesized and evaluated for their cytotoxic effect against HCT-15 colon and MCF-7 breast cancer cell lines using Sulforhodamine B (SRB) assay. The results showed that these compounds could exhibit a good cytotoxicity to both cell lines. In addition, these compounds were found to exhibit significant DNA-binding affinity. Ultraviolet-visible light (UV-Vis) spectroscopy was conducted to determine the ability of the ligand under analysis. The effect of ligand complexation on DNA structure led to overall affinity constants of K(4a)=3.5×10(4) M(-1), K(4b)=6.4×10(4) M(-1), K(4c)=3.2×10(4) M(-1), and K(4d)=2.4×10(4) M(-1). Our findings could provide new evidence showing the relationship between the chemical structure and biological activity and may be useful for the discovery of new anti-cancer drugs.     

Synthesis,in silico and in vitro studies of new 1,4-dihydropiridine derivatives for antitumor and P-glycoprotein inhibitory activity

P-glycoprotein (P-gp) is one of the cell membrane pumps which mediate the efflux of molecules such as anticancer drugs to the extracellular matrix of tumor cells. P_gp is a member of the ATP-binding cassette (ABC) transporter family that is implicated in cancer multidrug resistance (MDR). Since MDR is a contributor to cancer chemotherapy failure, modulation of efflux pumps is a viable therapeutic strategy. In this study, new synthetic 1,4 dihydropiridine (DHP) derivatives containing thiophenyl substitution were tested as inhibitors of P-gp. Efflux assay was conducted to evaluate the intracellular accumulation of Rhodamine123 (Rh123) as a pump substrate. MTT assay, cell cycle analysis and in silico methods were also examined. Flow cytometric analysis revealed that synthetic DHP derivatives (15 µM) increased intracellular concentration of the substrate by 2–3 folds compared with verapamil as a standard P-gp inhibitor. MTT assay on EPG85-257P and its drug-resistant EPG85-257RDB cell line revealed antitumor effects (30–45%) for new DHP derivatives at 15 µM following 72 h incubation. However, MTT test on normal cell line showed negligible toxic effects. Finally combination of synthetic derivatives with doxorubicin showed that these compounds decrease IC50 of doxorubicin in resistant cell lines from 9 to 1.5 µM. Sub-G1 peak-related apoptotic cells showed a stronger effect of synthetic compounds at 5 µM compared with verapamil. Molecular dynamic results showed a high binding affinity between DHP derivative and protein at drug binding site. Findings of these biological tests indicated the antitumor activity and P-gp inhibitory effects of new 1,4-DHP derivatives.     

Design,synthesis, and anticancer evaluation of some novel thiourea,carbamimidothioic acid,oxazole, oxazolidine,and 2-amino-1-phenylpropyl-2-chloroacetate derived from L-norephedrine

A novel series of thiourea, carbamimidothioic acid, 4, 5-dihydrooxazole-2-thiol, oxazolidine-2thine, and 2-amino-1-phenylpropyl-2-chloroacetate derivatives was designed and synthesized using 2-amino-1-phenylpropan-1-ol (L-norephedrine) as a strategic starting material. The structures of the newly synthesized compounds were established by elemental analyses, IR, and ¹H NMR and ¹³C NMR spectral data. The compounds were evaluated for their in vitro anticancer activity against various cancer cell lines. The corresponding acetamide, carbamimidothioic acid, and 2-2-amino-1-phenylpropyl-2-chloroacetate derivatives showed almost the same activity as the standard drug doxorubicin against human breast cancer cell line (MCF-7). Also, the acetamide and 2-thioxoimidazolidin-4-one derivatives exhibited higher activity than the reference drug doxorubicin against human colon cancer cell line (HCT 116).