Synthesis and anticancer study of 9-aminoacridine derivatives

Acridine and its derivatives, well known as DNA intercalates lead to cell cycle arrest and apoptosis. 9-Aminoacridine derivatives were synthesized, characterized and evaluated against lung cancer (A-549) cell line and cervical cancer (HeLa) cell line by MTT assay. Compound 9 exhibited potent anticancer activity with CTC₅₀ (13.75 & 18.75 μg/ml) for cervical cancer cell (HeLa) line and lung cancer cell (A-549) line respectively. In vitro short term cytotoxicity evaluation of compound 9 was carried out by Dalton’s Lymphoma Ascites (DLA) with percentage growth inhibition CTC₅₀ (337.5 μg/ml). Compound 7 also exhibited good anticancer activity with CTC₅₀ (31.25 & 36.25 μg/ml) for cervical cancer cell (HeLa) line and lung cancer cell (A-549) line respectively. Further in vivo study of newly synthesized 9-aminoacridine derivative can give a ray of light in the field of anticancer drugs.     

Synthesis and antiproliferative activity of novel A-homo-B-norsteroid thiadiazole derivatives

Using cholesterol as a starting material, two novel steroidal thiadiazole derivatives possessing a structure of A-homo lactam and a B-nor steroidal skeleton were designed and synthesized by six steps of reactions, and their antiproliferative activities were assayed against various cancer cell lines. The result shows that compound 7b displays an excellent selective inhibition to A-549 (human lung carcinoma) cancer cell lines with an IC₅₀ value of 8.0 μM.     

Gold-catalyzed oxazoles synthesis and their relevant antiproliferative activities

Nine 5-aryl-2-methyloxazole derivatives were synthesized via gold-catalyzed alkyne oxidation. All of the compounds have been screened for their antiproliferative activities against MCF-7 cell （human breast carcinoma）, A549 cell （human lung carcinoma） and Hela cell （human cervical carcinoma） lines in vitro. The results revealed that compounds 1b, 1c and 1d exhibited strong inhibitory activities against the MCF-7 cell lines （with ICso values of 4.6, 9.7 and 2.2 μmol/L, respectively）.     

Anticancer and antimicrobial evaluation of newly synthesized steroidal 5,6 fused benzothiazines

A series of new 5α-cholestano [5,6-b] benzothiazines (4–6) has been synthesized by the reaction of 5α-cholestan-6-one (1–3) with 2-aminothiophenol in the presence of iodine. The structures of newly synthesized compounds have been established on the basis of spectral and analytical data. Compounds (1–6) were screened for in vitro anticancer activity against the human cancer cell lines; SW480 (colon adenocarcinoma cells), A549 (lung carcinoma cells), HepG2 (hepatic carcinoma cells) and HeLa (cervical cancer cells) using MTT assay during which the products (4–6) showed marked increase in anticancer activity and in particular, compound 6 showed IC₅₀ = 13.73 μmol L⁻¹ against HeLa cells, being more effective than Doxorubicin against the same cells. Compounds 4 and 6 also showed minimum IC₅₀ of 15.83 μmol L⁻¹ and 16.89 μmol L⁻¹ against HepG2 and A549 cells, respectively. Compounds (1–6) were also tested for in vitro antimicrobial activity against different bacterial as well as fungal strains during which newly synthesized compounds (4–6) were found more potent than starting compounds (1–3). Compound 4 was found to be more potent than the reference drug, Chloramphenicol, in the case of Escherichia coli while compound 5 was found almost equally potential antifungal agent against P. marneffei in comparison with the reference drug, Nystatin.     

Design,synthesis and biological evaluation of novel 2-phenyl-4,5,6,7-tetrahydro-1H-​indole derivatives as potential anticancer agents and tubulin polymerization inhibitors

A new series of 2-phenyl-4,5,6,7-tetrahydro-1H-?indole derivatives as tubulin polymerization inhibitors were synthesized and evaluated for the anti-proliferative activities. All newly prepared compounds were tested for their antiproliferative activity in vitro on the human breast cancer cell line (MCF-7) and human lung adenocarcinoma cell line (A549). Among them, compound 7b with a 4-methoxyl substituent at the phenylhydrazone moiety exhibited the most potent anticancer activity against MCF-7 and A549 with IC₅₀ values of 1.77 ± 0.37 and 3.75 ± 0.11 μM, respectively. Interestingly, 7b displayed significant selectivity in inhibiting cancer cells over LO2 (normal human liver cells). Further mechanism studies revealed that 7b significantly arrested cell cycle at G2/M phase and induced apoptosis in a dose-dependent manner. Additionally, 7b effectively inhibited tubulin polymerization with an inhibitory manner similar to that of colchicine. Furthermore, molecular docking study suggested that 7b had high binding affinities for the colchicine binding pocket of tubulin. Hence, this study demonstrates for the first time that tetrahydroindole can be used as a functional group for the design and development of new tubulin polymerization inhibitors.     

Design,synthesis and biological evaluation of quinazolin-4(3H)-one Schiff base conjugates as potential antiamoebic agents

In an effort to develop novel antiamoebic scaffolds having better efficacy than the standard drug metronidazole (IC₅₀ = 1.80 μM) used against Entamoeba histolytica, quinazolin-4(3H)-one Schiff base conjugates were synthesized and evaluated against HM1: IMSS strain of E. histolytica. Out of the thirteen compounds (S2-S14), six compounds (S2, S3, S4, S5, S6 and S11) were found to be better inhibitors than metronidazole and showed low cytotoxicity on HeLa cells, a cervical cancer cell line. The structure of intermediate compound S1 was confirmed by crystal structure studies.     

Design, synthesis and antiproliferative activities of novel 5H-pyridazino[4,5-b]indoles

A novel series of 5H-pyridazino[4,5-b]indoles were designed and synthesized in order to find novel potent anticancer compounds.The structures were confirmed by ~1H NMR and MS.Their antiproliferative activities against two cancer cell lines were tested by the MTT method in vitro.Three of compounds (1e,1g,and 1h) exhibited potent antiproliferative activities,especially compound 1h (with IC_(50) values of 5.2μmol/L and 1.9μmol/L against Bel-7402 and HT-1080,respectively).The preliminary structure-activity relationships of 5H-pyridazino[4,5-b]indole derivatives were discussed.     

Synthesis,spectral characterization,theoretical, antimicrobial,DNA interaction and in vitro anticancer studies of Cu(II) and Zn(II) complexes with pyrimidine-morpholine based Schiff base ligand

Novel Cu(II) (1) and Zn(II) (2) complexes with 4-(1-(4-morpholinophenyl)ethylideneamino)pyrimidine-5-carbonitrile) (L) have been synthesized and characterized by various spectroscopic and analytical techniques. DFT (density functional theory) studies result confirms that, LMCT mechanism have been done between L and M(II) ions. The antimicrobial studies indicate that the ligand L and complexes 1 & 2 exhibit higher activity against the E. coli bacteria and C. albicans fungi. The groove binding mode of ligand L and complexes 1 & 2 with CT-DNA have been confirmed by electronic absorption, competitive binding, viscometric and cyclic voltammetric studies. The electronic absorption titration of ligand L and complexes 1 & 2 with DNA have been carried out in different buffer solutions (pH 4.0, 7.0 & 10.0). The K_b values of ligand L and complexes 1 & 2 are higher in acidic buffer at pH 4.0 (K_b = 2.42 × 10⁵, L; 2.8 × 10⁵, 1; 2.65 × 10⁵, 2) and the results revealed that, the interaction of synthesized compounds with DNA were higher in the acidic medium than basic and neutral medium. Furthermore, CT-DNA cleavage studies of ligand L and complexes 1 & 2 have been studied. The in vitro anticancer activities results show that complexes 1 & 2 have moderate cytotoxicity against cancer cell lines and low toxicity on normal cell line than ligand L.     

Synthesis and antitumor activity of water-soluble poly(aminoheterocyclic amine)s (I): N,N,N'''',N''''-tetra[2-(4-amino-5-substituted-s-triazol-3-yl sulfanyl)ethyl] -1,4-benzyldiamine salts

Five water-soluble poly(aminoheterocyclic amine)s containing s-triazole ring were synthesized as respective HC1 salts (5a-5e). Biological activities in L1210 (murine leukemia) and Chinese hamster ovary (CHO) cell lines were investigated via IC50 cytotoxicity determinations. The tide compounds represented moderate cytotoxicity (low IC50 values between 15 and 68μmol/L) in L1210 but high cytotoxicity (lower IC50 values: 0.25,0.018,0.014μmol/L for Sa-5e, respectively) in CHO cell lines, while the corresponding HC1 salts of the intermediates (3a-3e) without polyamine tether and starting materials amino-s-triazoles (1a-1e) showed poor or no activities against the above cell lines.     

Two new dimmeric xanthanolides isolated from Xanthium mogolium Kitag plant

Two xanthanolide-type dimmers, namely Mogolide D (4) and Mogolide E (5) are isolated from the aerial parts of Xanthium mogolium Kitag plant collected from Heilongjiang province, China. The dimmers’ relative structures are elucidated on the basis of HRESIMS, IR spectrum and NMR spectroscopy. The absolute configurations of them are assigned with ECD spectra. The biosynthetic pathway of the two dimmers is also proposed. Besides, Mogolide D (4) and Mogolide E (5) are tested against MDA-MB-231 breast cancer cell line with IC₅₀ 8.46 μM and 19.20 μM, respectively.     

In vitro evaluation of Radachlorin® sensitizer for photodynamic therapy

This paper reports the evaluation of a new photosensitizer, Radachlorin® in comparison with one of its well known components but used solely, Chlorin e₆. The photodynamic properties and cell uptake and localisation of the two drugs were compared. In vitro studies were conducted on human adenocarcinoma cells (HT29) and lung carcinoma cell line (A549). Both dyes showed an absorption maximum between 640 and 650 nm, but those absorption peaks are enhanced by interactions with serum, with a shifted maximum at 661 and 664 nm, and much higher absorbance. As Radachlorin® is constituted of different products and as photoreactivity is dependent on absorbed light energy, we chose to adapt concentrations so that both drugs had the same absorption at the irradiation wavelength (664 nm) for photoreactivity tests, and express concentrations in optical density at 664 nm. The capacity of the two drugs to generate Reactive Oxygen Species was identical, but on HT29 cells, Radachlorin® reaches its optimal LD50 sooner than Chlorin e₆. Radachlorin® LD50 on HT29 cells was 0.0251 OD_664nm after 2 h and 0.0672 OD_664nm for Chlorin e₆ for a 20 J cm^?2 irradiation. Radachlorin® gave very similar results on A549 cells, LD50 being 0.05 for 5 J irradiation, and 0.026 for 10 and 20 J cm^?2. Pharmacokinetics using fluorescence showed that, even if Radachlorin® quickly crossed HT29 (a human colonic cancer line) cell membrane, cellular distribution evolved from a diffuse cytoplasmic repartition 1 hour after Radachlorin® addition to a delimited localisation into organelles all around the nucleus. Radachlorin® intracellular fluorescence decreased after 4 h, whereas we did not observe a decrease of Chlorin e₆ intracellular fluorescence for times up to 24 h. In both case, a quick decline was observed as soon as the culture medium was replaced with a drug-free one. Radachlorin® appears to be an excellent photosensitizer, with similar phototoxicity to Chlorin e₆ on cell cultures, but with quicker kinetics, which could be an improvement if confirmed on further in vivo studies.     

The anti-lung cancer activity of propylene tethered dihydroartemisinin-isatin hybrids

Nineteen propylene tethered dihydroartemisinin-isatin hybrids 5a-g and 6a-l were designed, synthesized, and screened for their in vitro antiproliferative activity against three lung cancer cell lines, inclusive of drug-sensitive (A549), doxorubicin-resistant A549 (A549/DOX) and cisplatin-resistant A549 (A549/DDP) cell lines. The cytotoxicity of the synthesized hybrids towards normal lung epithelial cell line (BEAS-2B) was also assessed to evaluate the selectivity. The structure-activity relationship (SAR) elucidated that (1) alkyloxylimino fragment at C-3 position of isatin moiety were more favorable than the carbonyl and benzoxylimino, and the relative contricution order was methoxylimino > ethoxylimino > carbonyl > benzoxylimino; halogen atom at C-5 or C-6 position of isatin fragment could enhance the activity. Among them, hybrid 6f (IC₅₀: 21.7–28.9 μM) showed promising activity against the three tested lung cancer cell lines, and the activity was not inferior to that of cisplatin (IC₅₀: 19.7 and 66.9 μM) and doxorubicin (IC₅₀: 54.3 and 15.1 μM) against multidrug-resistant A549/DOX and A549/DDP lung cancer cell lines. In addition, hybrid 6f (IC₅₀: >100 μM) was non-cytotoxic towards normal lung epithelial cell line (BEAS-2B), and the RI values of hybrid 6f were 1.12 and 1.33. Further, hybrid 6f also possessed acceptable stability in mouse and human microsomes. Accordingly, hybrid 6a was a promising anti-lung cancer chemotherapeutic candidate and merited further evaluations.     

Synthesis,crystal structures and spectroscopic properties of two new organotin (IV) complexes and their antiproliferative effect against cancerous and non-cancerous cells

Cancer has become a leading cause of death worldwide, which is responsible for 7.6 million cancer deaths according to GLOBOCAN survey conducted in 2008. The exploration of cis-platin analogues (carboplatin, lobaplatin, nedaplatin, oxaliplatin) and their incorporation to the treatment of cancer patients has further led interest in exploring metal-based anticancer drugs. The current study describes the synthesis of two new tetra-coordinated mono- and tetranuclear organotin(IV) carboxylate complexes and their in vitro anticancer studies. Each one of the complexes (1–2) has been characterized by analytical (micro- and gravimetric analysis) and spectroscopic (FTIR, ¹H, ¹³C, ¹¹⁹Sn-NMR) techniques. Furthermore, molecular structures of 1 and 2 were elucidated using X-ray crystallography. The characterization data showed that the coordination took place via oxygen atoms from the carboxylate anions to generate 1 as an organodistannoxane dimer and 2 as a mononuclear complex. Exceptionally, the NMR spectroscopic and X-ray crystallographic study showed that acetone molecules also took part in crystallizing 2. Both complexes were tested against three cancerous (colon cancer HCT 116, breast cancer MCF 7, leukemia K562) and one non-cancerous (3T3-L1) cell lines. Both complexes showed same IC₅₀ value (0.2 μM) against HCT 116, whereas for the other two cancer cell lines (MCF 7 and K562) and a normal cell line (3T3-L₁), 2 showed results better than 1. Importantly, the complexes showed exceptional activity against MCF 7 and K562 cell lines and the IC₅₀ values were calculated in nanomoles (MCF 7, IC_50s = 86.5 and 53.4 nM; K 562, IC_50s = 22.9 and 49.6 nM for 1 and 2, respectively). Both, 1 and 2, showed IC₅₀ values many times better than the standard drugs (5-FU, Tamoxifen, betulinic acid and cis-platin) used. Compared to cancerous cell lines, the complexes showed mild toxicity against normal cells (3T3-L1). Overall, two remained relatively effective.     

DNA binding,docking studies,artificial nuclease activity and in vitro cytotoxicity of newly synthesized steroidal 1H–pyrimidines

A new series of steroidal pyrimidines (7–9) has been synthesized by reacting steroidal thiosemicarbazones (4–6) with ethyl cyanoacetate. The compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS and analytical data. The interaction studies of compounds 7–9 with DNA were carried out by UV–vis and luminescence spectroscopy. Compounds (7–9) bind to DNA preferentially through electrostatic and hydrophobic interactions, with K_b values found to be 6.56 × 10³ M⁻¹, 1.54 × 10⁴ M⁻¹ and 9.34 × 10³ M⁻¹, respectively, indicating the higher binding affinity of compound 8 towards DNA. Gel electrophoresis pattern demonstrated that compound 8 shows strong interaction with DNA and that, during its cleavage activity with pBR322 DNA, it seems to follow the mechanistic pathway involving the generation of singlet oxygen and a superoxide anion, which are responsible for initiating DNA strand scission. The docking study suggested that the intercalation of compounds in between the nucleotide base pairs is due to the presence of a pyrimidine moiety in the steroid molecule. MTT assay was carried out to check the toxicity of new compounds 7–9 against the different human cancer as well as non-cancer cell lines A545, MCF-7, HeLa, HL-60, SW480, HepG2, HT-29, A549, 184B5, MCF10A, NL-20, HPC, and HPLF. Apoptotic degradation of DNA in the presence of steroidal pyrimidines 7–9 was analysed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay).     

A new cytotoxic salannin-class limonoid alkaloid from seeds of Azadirachta indica A. Juss

Azadiramide A (1), a new salannin-class limonoid alkaloid, inhibits growth of human breast cancer MDA-MB-231 cell line with IC₅₀ value of 2.70±0.63 μmol/L.     

Lewis acid-assisted olefin cross-metathesis reaction: an efficient approach for the synthesis of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin and evaluation of their antitumor activity

A series of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin (2a–g) were synthesized via Lewis acid-assisted olefin cross-metathesis reaction using Ti(OⁱPr)₄ 30 mol % and 10 mol % of Grubb’s second generation catalyst with good to excellent yields. Most of these compounds exhibited significant growth inhibitory effects on all the tested cancer cell lines and three compounds (2c, 2d and 2e) showed potent cytotoxic activity.     

Design and synthesis of novel water-soluble amino acid derivatives of chlorin p6 ethers as photosensitizer

Eight new water-soluble amino acid derivatives of chlorin p₆ ethers 6a-h were designed and synthesized using purpurin-18 (2) as key intermediate. All target compounds exhibited better phototoxicity than talaporfin and the most phototoxic compound 6d showed IC₅₀ values of 0.20 μmol/L against A549 cell and 0.41 μmol/L against B16-F10 cell, which represented 31- and 24-fold increase of PDT antitumor efficacy compared to talaporfin.     

Cytotoxic arylbenzofuran and stilbene derivatives from the twigs of Artocarpus heterophyllus

Four new natural products, including three arylbenzofurans named heterophyllenes A-C (1–3), and one stilbene named heterophyllene D (4), together with twenty-one known compounds were isolated from the twigs of Artocarpus heterophyllus and their structures elucidated by spectroscopic methods, mainly 1D and 2D NMR spectroscopy. The cytotoxic activity of selected compounds against KB, MCF-7 and NCI-H187 cell lines was evaluated. Heterophyllene C (3) exhibited cytotoxicity against the MCF-7 cell line with an IC₅₀ value of 12.56 μM. Additionally, the known compounds norartocarpin and artocarpin showed cytotoxic activity against MCF-7 and KB cell lines with IC₅₀ values of 10.04 and 13.57 μM, respectively. Both compounds also displayed cytotoxicity against the NCI-H187 cell line with values of 14.78 and 14.21 μM, respectively.     

Catharoseumine,a new monoterpenoid indole alkaloid possessing a peroxy bridge from Catharanthus roseus

Catharoseumine (1), a new monoterpenoid indole alkaloid possessing a unique peroxy bridge moiety, was isolated from the whole plants of Catharanthus roseus. Its structure was elucidated on the basis of NMR, IR, UV, and high-resolution mass spectrometric data, and its absolute configuration was determined by ECD and chemical methods. Catharoseumine (1) exhibited cytotoxicity against HL-60 cell line with IC₅₀ value of 6.28 μM and potential inhibition against Plasmodium falciparum falcipain-2 (IC₅₀ = 4.06 μM). A plausible biogenetic pathway of 1 was also proposed.     

Diazenyl schiff bases: Synthesis,spectral analysis,antimicrobial studies and cytotoxic activity on human colorectal carcinoma cell line (HCT-116)

A series of diazenyl schiff bases have been synthesized by reaction of salicylaldehyde containing azo dyes with various substituted aniline derivatives in the presence of acetic acid as catalyst. The structures of diazenyl derivatives were determined by FTIR, UV–vis, ¹H NMR, ¹³C NMR, CHN analysis, fluorimetric and mass spectroscopic studies. The synthesized derivatives were screened for their in vitro antimicrobial activity against various Gram-positive (S. aureus, B. subtilis, B. cereus), Gram-negative (S. typhi, S. enterica, E. coli, P. aeruginosa) bacterial and fungal (C. albicans, A. niger and A. fumigatus) strains, using cefadroxil (antibacterial) and fluconazole (antifungal) as standard drugs. The diazenyl schiff bases were also screened for their cytotoxicity against human colorectal carcinoma cell line (HCT-116) using 5-fluorouracil as standard drug by Sulforhodamine-B Stain (SRB) assay. The schiff bases exhibited significant activity toward both Gram-positive, Gram-negative bacterial and fungal strains. Most of the synthesized derivatives showed high activity against S. enterica. 4-((2,5-Dichlorophenyl)diazenyl)-2-((3-bromophenylimino)methyl)phenol (SBN-40) was found to be very active against S. aureus, B. cereus and E. coli, with MIC = 0.69 (µM/ml × 10²). The compound 4-((2-bromophenyl)diazenyl)-2-((4-nitrophenylimino)methyl)phenol (SBN-13) possessed comparable activity (IC₅₀ = 7.5 µg/ml) to the standard drug 5-fluorouracil (IC₅₀ = 3.0 µg/ml) against human colorectal carcinoma cell line (HCT-116).