Design and synthesis of A- and D ring-modified analogues of luotonin A with reduced planarity

A small library of A- and D-ring modified luotonin-inspired heterocyclic systems have been synthesised in moderate to good yields following a six-step route that starts from phenylalanine and has the final key stage an intramolecular Povarov reaction of imines obtained from a tetrahydroquinoline-derived alkynyl aldehyde and various arylamines.     

Synthesis and anticancer activity of some novel benzothiazole-thiazolidine derivatives

Sixteen new 2-(benzothiazol-2-ylthio)-N′-(3-substituted-4-(3,4-substitutedphenyl)thiazol-2(3H)-ylidene)acetohydrazide derivatives (4a-4p) were synthesized. The structures of the synthesized compounds were elucidated using FT-IR, ¹H-NMR, ¹³C-NMR, and HRMS spectral data. Anticancer activity of the compounds 4a-4p against C6 (rat brain glioma) and A549 (human lung adenocarcinoma) cell lines was evaluated by using MTT, inhibition of DNA synthesis, and flow cytometric analysis assays. According to MTT assay, 4a and 4d were found to be the most active compounds against C6 cell line with an IC₅₀ value of 0.03 mM. Moreover, IC₅₀ values of 4a (0.2 mM) and 4d (0.1 mM) against NIH3T3 (mouse embryo fibroblast cell line) were higher than their IC₅₀ values (0.03 mM) against C6 cell line. Accordingly, selectivity of compound 4a against C6 cell line was two-fold higher than that of compound 4d. Flow cytometry analysis showed that these compounds display anticancer activity by inducing apoptosis. As a result, compound 4a has a remarkable anticancer activity and a good selectivity towards C6 cell lines.     

Solanopubamine,a rare steroidal alkaloid from Solanum schimperianum: Synthesis of some new alkyl and acyl derivatives,their anticancer and antimicrobial evaluation

Solanopubamine (3β-amino-5α, 22αH, 25βH-solanidan-23β-ol), a steroidal alkaloid was isolated from the alkaloidal fraction of Solanum schimperianum in significant yield. Its structure was established by IR, positive ESI-MS, 1D and 2D NMR. The presence of -3β-NH₂ and -23β-OH groups was achieved through methylation, acetylation or coupling with octadecanoic and undec-11-enoic acids to produce six derivatives (2–7). Their structures were confirmed by spectroscopic analyses. Solanopubamine and semi-synthetic analogs are investigated for their in vitro cytotoxicity against a panel of human cancer cell lines and anti-microbial activity. Solanopubamine showed good antifungal activity only against Candida albicans and C. tenuis with MIC of 12.5 μg/mL. Semi-synthesized compounds (2–7) have failed to show anti-tumor and anti-microbial activities.     

A new series of titanocene dichloride derivatives bearing cyclic alkylammonium groups: Assessment of their cytotoxic properties

Ten new water soluble titanocene dichloride derivatives have been synthesized and characterized and their cytotoxicities against the human lung cancer cell line A549 have been assessed. The potencies of the compounds vary greatly, but dicationic 3-picolylium and 4-picolylium compounds exhibit IC₅₀ values that are unusually low for this class of compounds. In view of their potency against A549 cells, three of the new complexes were tested further on additional human cell lines including the small cell lung cancer cell line H69, the widely used cervical carcinoma cell line HeLa, the ovarian carcinoma cell line A2780 and its cisplatin resistant derivative A2780/CP. All three compounds exhibited potencies in all cell lines comparable to or better than those observed with the A549 cells, while one complex is actually more potent than cisplatin for HeLa cells.     

Molecularly imprinted microspheres for the anticancer drug aminoglutethimide: Synthesis,characterization, and solid‐phase extraction applications in human urine samples

Molecularly imprinted microspheres (MIMs) for the anticancer drug aminoglutethimide (AG) were synthesized by aqueous suspension polymerization. The expected size and diameter of MIMs are controlled easily by changing one of the surfactant types, ratio of organic‐to‐water phase or stirring rate during polymerization. The obtained MIMs exhibit specific affinity toward AG with imprinting factor of 3.11 evaluated with a chromatographic model. The resultant MIMs were used as the SPE materials for the extraction of AG from human urine. A molecularly imprinted SPE (MISPE) method coupled with HPLC has been developed for the extraction and detection of AG in urine. Our results showed that most impurities from urine can be removed effectively after a washing step and the AG has been enriched effectively after MISPE operation with the recovery of >90% (n = 3). The developed MISPE–HPLC method could be used for enrichment and detection of AG in human urine.     

Liquid chromatographic determination of cis-platin as platinum(II) in pharmaceutical preparation, serum and urine samples of cancer patients

Spectrophotometric and high performance liquid chromatographic (HPLC) methods have been developed for the determination of cis-platin and carboplatin based on the pre-column derivatization of platinum(II) with 2-acetylpyridine-4-phenyl-3-thiosemicarbazone. The complex was extracted in chloroform with molar absorptivity of 2.2 × 10⁴ L mol⁻¹ cm⁻¹ at 380 nm. The complex eluted from a Phenomenex C-18 (150 mm × 4.6 mm i.d.) column with methanol:water:acetonitrile:tetrabutyl ammonium bromide (1 mM) (44:30:25:1, v/v/v/v) with a flow rate of 1 ml/min and UV detection at 260 nm. Ruthenium(IV) and selenium(IV) also separated completely. The linear calibration curve was with 0.5-12.5 μg/ml and detection limit of 10 ng/ml platinum(II).The analysis of cis-platin and carboplatin injections by spectrophotometric and HPLC methods indicated relative standard deviation (R.S.D.) of 0.66-2.1%. The method was used for the determinations of cis-platin in serum and urine of cancer patients after chemotherapy and platinum contents were found 148-444 and 50-90 ng/ml with R.S.D. of 0.3-3.0 and 0.6-2.4% for the serum and urine, respectively. The recovery of platinum(II) from serum was 97% with R.S.D. 2.2%.     

Determination of the stereoisomers in aqueous medium and serum and validation studies of racemic aminoalkanol derivatives of 1,7‐dimethyl‐8,9‐diphenyl‐4‐azatricyclo[5.2.1.02,6]dec‐8‐ene‐3,5,10‐trione,potential new anticancer drugs,by capillary electrophoresis

A new method for the determination of the stereoisomers, in aqueous medium and serum, of the racemic aminoalkanol derivatives I and II of 1,7‐dimethyl‐8,9‐diphenyl‐4‐azatricyclo[5.2.1.0^2,6]dec‐8‐ene‐3,5,10‐trione, which were found in earlier studies to be potential anticancer drugs, was developed and validated. The optimized conditions included 25 mM phosphate buffer adjusted to pH 2.5, containing γ‐cyclodextrin at a concentration of 5% m/v, as background electrolyte, an applied voltage of +10 kV, and a temperature of 25°C. Separations were carried out using a fused‐silica capillary. The developed method of determining the enantiomers of compounds I(S), I(R) and II(S), II(R) was characterized by the following parameters: a detection time within 10.8 min, a detection limit in the range of 141.2–141.7 ng/mL using the UV absorption detection at 200 nm. Good linearity (R² = 0.9989–0.9998) was achieved within the range of concentrations studied. A very good extraction yield of 95.4–99.7% was achieved, and recoveries were carried out from both aqueous solutions and matrix serum. The repeatability of the method for peak areas with an accuracy of the determined concentrations of the analytes in the range of 1.43–1.89%, and limits of quantitation in the range of 432.4–436.3 ng/mL were achieved.     

Liquid chromatographic and mass spectrometric analysis of human serum acid alpha-1-glycoprotein

Human serum acid alpha-1-glycoprotein (AGP, orosomucoid) content of healthy individuals and cancer patients was measured, isolated and purified using a protocol of fast and biocompatible sample preparation, ion exchange and dye-ligand affinity chromatographic methods. In comparison to the healthy individuals significantly higher serum AGP levels were found in a wide spectrum of cancer patients, indicating its diagnostic value in the malignant disease. Oligosaccharide content of AGP samples was separated following PNGase F enzyme digestion and analysed by RP-HPLC and MALDI-TOF mass spectrometry. RP-HPLC and MALDI-TOF mass spectrometric analysis of sugar constituents of AGP specimen originated from selected cancer patients with high serum AGP levels indicated the appearance of anomal distribution of bi-, tri- and tetra-antennary oligosaccharide structures compared to the healthy controls.     

Liquid chromatographic analysis of doxazosin in human serum with manual and robotic sample preparation

A specific method for the determination of the antihypertensive drug doxazosin in human serum is described. The method utilizes the related drug prazosin as an internal standard and is based on a simple extraction scheme followed by analysis by reversed-phase ion suppression high-performance liquid chromatography (HPLC) on an alumina-based column with fluorescence detection. The method is completely automated with a flexible robotic system for the analysis of drugs in biological fluids. The robotic automation of the method allows a 20% increase in the sample throughput and the savings of about 7 man-hours a day. Both the manual and robotic procedures yield precise quantitative results over the therapeutically relevant concentration range of 0.5 to 20 ng/mL of serum.     

Synthesis and characterization of phenanthrene derivatives with anticancer property against human colon and epithelial cancer cell lines

A variety of polycyclic aromatic hydrocarbons have been synthesized and structurally characterized in our laboratory. Phenanthrene derivatives were efficiently prepared in excellent yields and high purity via a two-step sequence. Heck coupling yielded the corresponding diarylethenes, followed by classical oxidative photocyclization to achieve the expected phenanthrenes. First, we envisioned to synthesize a variety of substituted phenanthrenequinones. Second, we investigated the possibility of a dibenz[a,c]phenazine formation by addition of o-phenylenediamine after completion of the oxidation process. Moreover, because phenanthrenequinones are available so simply, it is likely that other uses will be found for these compounds. For example, 9,10-phenanthrenequinone can be sequentially reduced, alkylated, acetylated, and sulfonated. All the synthesized derivatives were evaluated for cytotoxic activity in vitro against the human epidermoid carcinoma epithelial cells Hep-2 and human colon carcinoma cells Caco-2 using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. From the structure–activity point of view, position and nature of the electron donating and electron withdrawing functional groups attached to the phenanthrene skeleton may contribute to the anticancer action. Interestingly, the analysis of the IC₅₀ values suggests that most compounds exerted cytotoxic effects with selectivity against both cancer cells. Among them, methyl 8-methyl-9,10-phenanthrenequinone-3-carboxylate 11d showed the highest potency with IC₅₀ values of 2.81 and 0.97 μg/mL.     

Synthesis and evaluation of in vitro anticancer activity of novel solasodine derivatives

<正>Solasodine 11 is a steroidal alkaloid with various biological activities.Herein,8 novel solasodine derivatives were synthesized and their effect on prostate cancer cell proliferation was assessed in vitro.Significant improvement in antiproliferative activity was achieved among some of the synthetic analogs.In particular,19 exhibited the most potent inhibitory effect against the proliferation of PC-3 cell line(IC_(50) = 3.91μmol/L).     

Design,synthesis and docking studies of new hydrazinyl-thiazole derivatives as anticancer and antimicrobial agents

Increase in the number of infections caused by pathogenic microbes in cancer patients has prompted the searcher to invest in the development of agents having dual anticancer and antimicrobial properties. The present study is concerned with synthesis and screening for anticancer and antimicrobial activity of a series of 5-hydrazinyl-2-(2-(1-(thien-2-yl)ethylidene)hydrazinyl)thiazole derivatives. The structure elucidation of the synthesized hydrazinyl thiazole derivatives was illustrated by spectroscopic and elemental analysis. All the newly synthesized compounds 5a-p were evaluated for in-vitro cytotoxic activity against breast carcinoma (MCF-7 cell line), hepatocellular carcinoma (HePG-2) and colorectal cancer (HCT-116) cell lines using MTT assay method. Compounds 5 g, 5h showed broad spectrum activity against three cancer cell lines with IC₅₀ ranged from 3.81 to 11.34 µM in compared to the reference drug Roscovitine (IC₅₀ = 9.32 to 13.82 µM), while compounds 5 l and 5 m were found to be more selective against HePG-2 and HCT-116 cell line (IC₅₀ = 9.29 and 8.93 µM respectively) and compound 5j was more selective against HePG-2 and MCF-7 cell lines (IC₅₀ = 6.73 and 10.87 µM respectively). The inhibitory activity of the most promising compounds was tested against the EGFR and ARO enzymes and were further tested for apoptosis and Annexin V/PI staining. The results of enzyme-based tests revealed that the tested compound 5j has a dual inhibitory effect on the EGFR and ARO enzymes with IC₅₀ = 82.8 and 98.6 nM respectively in compared to the reference drugs Erlotinib and Letrozole (IC₅₀ = 62.4 and 79 nM respectively). Furthermore, the majority of the tested hydrazinyl thiazole derivatives exhibited significant antimicrobial activity against the used pathogenic microbes species. Compounds 4b, 5h, 5j and 5 m exerted a good antibacterial and antifungal activity against all tested pathogenic microbes. Therefore, it was concluded that compounds 5 h, 5j and 5 m proved to possess dual anticancer and antimicrobial agent and may serves as a useful lead compounds in search for further modification or derivatization to give more potent and selective agents.     

Design and synthesis of some novel pyridothienopyrimidine derivatives and their biological evaluation as antimicrobial and anticancer agents targeting EGFR enzyme

A new series of pyridothienopyrimidine derivatives was designed and evaluated as antimicrobial and anticancer agents. The target compounds were synthesized starting with 3-aminothieno[2,3-b]pyridine-2-carboxamide derivative 1 which underwent cyclocondensation reaction with aromatic aldehydes to give the key intermediates 2a,b. By further treatment of 2a,b with various reagents, the target 2,4-disubstituted-pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidines 3a,b–11a,b were obtained. To evaluate the antimicrobial activity of the new compounds, they were tested against five bacterial and five fungal strains. Compounds 6c, 8b, 9a and 9b revealed the most significant antimicrobial activity against the tested microorganisms with MIC values range (4–16 μg/mL). Also, compounds 2a,b–11a,b were screened for their in vitro cytotoxic activity against HepG-2 and MCF-7 cancer cell lines compared with doxorubicin and cisplatin as references drugs. Moreover, compounds (2b, 4a, 6a, 7b, 7c and 9a) which exhibited the most potent anticancer activity, were further subjected to EGFR^WT enzyme inhibition assay utilizing erlotinib as a standard drug. The compounds 6a, 7b, 7c and 9a which showed the most promising suppression effects were also evaluated as inhibitors against the mutant forms EGFR^L858R and EGFR^T790M. The 4-aminopyrazolone analogue 9a showed superior anticancer activity against both HepG-2 and MCF-7 cell lines (IC50 = 1.27, 10.80 μM, respectively) and more potent enzymatic inhibition activity against EGFR^WT and its mutant forms EGFR^L858R and EGFR^T790M than that obtained by erlotinib (IC₅₀ = 0.021, 0.053, 0.081 µM, respectively, IC_50erlotinib; 0.027, 0.069, 0.550 µM, respectively). Finally, the molecular docking study showed good binding patterns of the most active compounds with the prospective target EGFR^WT.     

Liquid chromatographic analysis of clonazepam in human serum with solid-phase (Bond-Elut) extraction

A simple, sensitive, selective and precise liquid-column chromatographic assay for clonazepam is described, in which 1 ml of serum containing 50 micrograms/l methylclonazepam as an internal standard is extracted by elution from a Bond-Elut column with 400 microliter of methanol. An aliquot of the eluate is injected on to a reversed-phase column and eluted with a mobile phase of acetonitrile--phosphate buffer (30:70) at a flow-rate of 2 ml/min at a column temperature of 50 degrees C. Detection is at 254 nm. Chromatography is complete in 12 min. A sensitivity of 2 ng/ml is attained when 1 ml of serum is extracted. Analytical recovery of the clonazepam added to serum ranged from 91% to 99% with a coefficient of variation of 6.0%. This assay for clonazepam has good precision, with coefficients of variation of 11% at 15 ng/ml and 2.6% at 50 ng/ml. There was no interference from any of the commonly used antiepileptics.     

Liquid chromatographic trace enrichment with on-line capillary gas chromatography for the determination of organic pollutants in aqueous samples

Trace enrichment for the GC analysis of a series of chlorinated pesticides and polychlorinated biphenyls (PCBs) in aqueous samples has been achieved through a simple on-line technique involving sorption on an LC micro-precolumn followed by direct elution into a gas chromatograph with hexane. A 5-m retention gap coupled to the capillary GC column served as the recipient of a relatively large sample volume (ca. 100 μl) introduced into the GC. Partially concurrent solvent evaporation during sample introduction allowed a large sample capacity. Recoveries of more than 95% were observed for the majority of the compounds studied. Using 1.0 ml aqueous samples, detection limits of less than 1 ppt were found. The applicability of the developed method was demonstrated for a river water sample.     

Synthesis,antimicrobial and anticancer activities of some new N-methylsulphonyl and N-benzenesulphonyl-3-indolyl heterocycles: 1st Cancer Update

A series of 1-(N-methyl 2a–c and N-benzenesulphonyl-1H-indol-3-yl)-3-aryl-prop-2-ene-1-ones 3a–c were prepared and allowed to react with urea, thiourea or guanidine and gave the pyrimidine derivatives 4a–c to 9a–c. Base catalyzed reaction of 2a–c or 3a–c with ethyl acetoacetate gave cyclohexanone derivatives 10a–c and 11a–c, respectively. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 12a–c and 13a–c, respectively. On the other hand, condensation of 2c or 3c with some hydrazine derivatives namely, hydrazine hydrate, acetyl hydrazine, phenyl hydrazine and benzyl hydrazine hydrochloride gave pyrazole derivatives 14a,b-17a,b, respectively. Moreover, reaction of 2c or 3c with hydroxyl amine hydrochloride gave isoxazole derivatives 18a,b. The newly synthesized compounds were tested for their antimicrobial activity and showed that, compounds 14a, 14b, 15a and 15b were found to be the most active ones of all the tested compounds toward Salmonella typhimurium (ATCC 14,028) compared to the reference drug chloramphenicol. Eighteen new compounds namely, pyrimidin-2(1H)-ones 4a–c and 5a–c, pyrimidin-2(1H)-thiones 6a–c and 7a–c and pyrimidin-2-amines 8a–c and 9a–c were tested for their in vitro cytotoxicity against human liver carcinoma (HEPG2), human breast cancer (MCF7) and human colon cancer (HCT-116) cell lines and showed that, compounds 4c, 5c, 6c, 8c and 9c were found to be the highly active compounds compared to the reference drug doxorubicin.     

Remarkable regioselectivities in the course of the synthesis of two new Luotonin A derivatives

Ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate reacts selectively with trimethylaluminium-activated 2-amino- or 4-aminobenzoic acid ethyl esters to give the corresponding anilides without self-condensation of the aminobenzoate building blocks. After propargylation, the quinazolinones were treated with Hendrickson's reagent, but only the para-substituted ester was found to undergo the expected [4 + 2] cycloaddition reaction, affording a new Luotonin A derivative. A different regioselectivity was observed with the ortho-substituted ester which affords a benzoxazinone under identical conditions. When the ester group in the ortho-substituted intermediate is replaced with a nitrile function, the outcome of the reaction with Hendrickson's reagent depends on the absence or presence of a base (DBU), yielding either a triphenylphosphonium-substituted iminobenzoxazine or a 4-cyano-substituted Luotonin A derivative.     

Synthesis and anticancer activity of the proposed structure of caldoramide,an N-peptidyltetramate from the cyanobacterium Caldora penicillata

The structure proposed in the literature for caldoramide, a formal pentapeptide metabolite of the marine cyanobacterium Caldora penicillata, was synthesised in 12 steps and 16% yield (longest linear sequence from isoleucine) following the strategy of a stepwise consecutive extension of an N-oligopeptidyl chain on a tetramate anchor. The synthetic product differed from the natural isolate in optical rotation, some NMR data, and cytotoxicities. Its antiproliferative effect on three human cancer cell lines was distinctly lower than that of related dolastatin 10 and belamide A.     

NMR analysis of antitumor drugs: Doxorubicin,daunorubicin and their functionalized derivatives

¹H, ¹H–¹H COSY and ¹³C NMR techniques were proven as effective methods for the analysis of functionalized doxorubicin (DOX) and daunorubicin (DAU) derivatives. These compounds represent important drug conjugate intermediates that can be coupled to a variety of nanocarriers. NMR spectroscopy was shown to be an efficient method for following the progress of drug modification and can also be useful for evaluation of the functionalized structures purity. Additionally, a correction of the chemical shifts reported in the literature for the relevant drugs e.g. DOX·HCl and DAU·HCl is presented.