Synthesis and Antiproliferative Activity of New Thiosemicarboxamide Derivatives

To discover new anticancer agents, two series of thiosemicarboxamide derivatives were synthesized and evaluated for their antiproliferative activity against human cancer cells in vitro. Most target compounds (especially 3f , 3g , and 3h ) exhibit potent antiproliferative activity against HeLa cells. Importantly, compound 3h , bearing a 4-methylphenyl substituent at N position of thiourea moiety, has significant and broad-spectrum inhibitory activities against cancer cells (HepG2, HeLa, MDA-MB231, A875, and H460 cells) with low IC₅₀ values (<5.0 μM) and shows low toxicity to normal LO2 and MRC-5 cells. Further studies show that compound 3h exerts high inhibitory activity in cancer cells by inducing the G2/M-phase arrest of cancer cells. Collectively, this study presents compound 3h as a new entity for the development of cell cycle arrest inducers for the treatment of cancer.     

Synthesis and Antioxidant Activity of New Norcantharidin Analogs

New norcantharidin analogs were designed and obtained as compounds with biological activity. As a starting material, exo‐7‐oxabicyclo[2.2.1]heptane‐2,3‐dicarboxylic acid anhydride was used. Three groups of compounds: dicarboximides, triazoles and thiazolidines were obtained in multistep reactions. The ¹H‐ and ¹³C‐NMR spectra were used to confirm the structures of all obtained products and they were in agreement with the proposed structure of substances. All derivatives were screened for their antioxidant activity. The most promising group was dicarboximides ( 1 – 4 , 6 ). Derivatives 2–4 displayed antioxidant activity with EC₅₀=7.75–10.89 μg/ml, which may be comparable to strong antioxidant Trolox (EC₅₀=6.13 μg/ml). Excellent activity with EC₅₀=10.75 μg/ml also presented norcantharidin analog with 1,2,4‐triazole system ( 12 ).     

Synthesis and Hybridization Studies of Oligonucleotide Sequences with Modified Fluorescent Nucleoside Analogs

Abstract

Two complementary oligodeoxynucleotide hexamers CATGAA and TTCATG and a pentamer with a fluorescent nucleoside analog viz. 9-N-(2′-deoxy-β-D-ribofuranosyl) carbazole (C*) incorporated into it, TTC*ATG were synthesized and characterised by spectroscopic and chromatographic studies. The comparative fluorescent studies of the two nucleoside analogs viz. 9-N-(2′-deoxy-β-D-ribofuranosyl) acridone and its carbazole analog (C*) have been carried out under different experimental conditions. The effect on fluorescence by incorporation of (C*) into the sequence and its subsequent hybridization with the complementary sequence have been studied.     

Efficient Synthesis of a New L-Shaped Dimer of Naphthalene,and Its Analogs

Efficient syntheses of 14H-dinaphtho[1,8-bc:1′,8′-fg]oxocin-14-one (2), 14H-dinaphtho[1,8-bc:1′,2′-f]oxepin-14-one (3), and 2,2′(2H,2′H)-spirobi[naphtho[1,8-bc]furan] (9) are described. The putative structure of 2 has been reported previously, but the synthetic route was not reproducible. 7H-Dibenzo[c,h]xanthen-7-one (4), a known compound, was obtained by a different method. Possible reaction mechanism are proposed.     

Synthesis and Biophysical Studies of Modified Oligonucleotides Containing Acyclic Amino Alcohol Nucleoside Analogs

Abstract

Novel serine derivative of thymine was prepared and incorporated into oligonucleotides. These modified oligonucleotides were studied for their binding affinity with complementary DNA/RNA.     

Synthesis,Antiproliferative, and Antiviral Evaluation of Certain Acyclic 6-Substituted Pyrrolo[2,3-D]-pyrimidine Nucleoside Analogs Related to Sangivamycin and Toyocamycin

Abstract

A number of 6-substituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine and 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidine derivatives related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for their biological activity. Treatment of 2-amino-5-bromo-3,4-dicyanopyrrole (2) with triethylorthoformate, followed by alkylation via the sodium salt method with either 2-(acetoxyethoxy)methyl bromide or (1,3-diacetoxy-2-propoxy)methyl bromide, furnished the corresponding N-substituted pyrroles 3a and 3b. These compounds were then smoothly converted to the requisite deprotected 4-amino-6-bromopyrrolo[2,3-d]-pyrimidine-5-carbonitriles 5a and 5b (toyocamycin analogs) by methanolic ammonia. The 6-amino-derivatives were obtained by a displacement of the bromo group with liquid ammonia. Conventional functional group transformations involving the 5-cyano group furnished the 5-carboxamide (sangivamycin) and 5-thioamide analogs. Compounds substituted at the 7-position with a ribosyl moiety were active against human cytomegalovirus (HCMV) at micromolar concentrations, but the apparent activity was not selective. The 7-ribosyl compounds also had no activity against human immunodeficiency virus (HIV), though they were all cytotoxic. The new compounds were also evaluated against HCMV, herpes simplex virus type I (HSV-1), HIV, and also for their ability to inhibit the growth of L1210 murine leukemic cells in vitro. None of these compounds with (2-hydroxyethoxy)methyl substituents or 7-(1,3-dihydroxy-2-propoxy)methyl substituent at N-7 showed significant cytotoxicity toward L1210, or toward uninfected human foreskin fibroblasts (HFF cells), and KB cells. Nor were they cytotoxic in human lines CEM or MT2. Only compound 4a was found to be active against HCMV, having an IC₅₀ of 32 μM.     

几种金属单质及其合金修饰电极电解合成L-半胱氨酸的研究

用几种氢过电位较高的金属Ｓｎ、Ｂｉ、ＮｉＺｎ以及Ｃｕ修饰铅电极,用于电解合成Ｌ－半胱氨酸的反应,首先筛选出性能较好的Ｓｎ、Ｎｉ、Ｚｎ电极,然后对该三种金属的合金进行研究,筛选出性能优越的（Ｎｉ－Ｓｎ）／Ｐｂ电极,电极活性大为提高,反应同期转化率明显提高。     

Synthesis of Brassinolide Analogs with a Modified Ring B and Their Plant Growth-promoting Activity

7-Aza, 7-thia and 6-deoxo analogs of (22S,23S)- and (22R,23R)-homobrassinolide were synthesized. They were found to possess weak bioactivity in a lamina-inclination test.     

Synthesis and Testing of New Modified Nucleosides

Abstract

New efficient routes for the high-yielding synthesis of several classes of modified nucleosides have been developed. We have prepared both the D- and L-enantiomers of the methylene-expanded oxetanocin isonucleosides 1a-c and the L-2′,3′-dideoxy isonucleosides 2abc (both the oxa and thia analgoues) as well as new routes for the preparation of L-ribose and 2-deoxy L-ribose 3ab and their modified nucleosides 4.     

Synthesis and Biological Properties of New Phosmidosine Analogs Having an N-Acylsulfamate Linkage

A new phosmidosine analog 10, in which the proline and 8-oxoadenosine moieties were linked by an N-acyl sulfamate linkage, was successfully synthesized by the sulfamoylation of an 8-oxoadenosine derivative 5 followed by coupling with an L-proline derivative 8. An L-alanine-substituted derivative 13 and its derivative 14 without the alanyl residue were also synthesized. The morphological reversion activity of these synthetic compounds in v-src ^ts NRK cells and their antitumor activity in L1210 and KB cells were studied. As the result, neither L-proline- nor L-alanine-substituted phosmidosine analogs 10 and 13 showed any antitumor activity. Contrary to these results, the derivative 14 lacking the amino acid residue showed potent antitumor activities against cancer cells.     

Synthesis and secretion of GnRH

Comprehensive studies have provided a clear understanding of the effects of gonadal steroids on the secretion of gonadotropin releasing hormone (GnRH), but some inconsistent results exist with regard to effects on synthesis. It is clear that regulation of both synthesis and the secretion of GnRH are effected by neurotransmitter systems in the brain. Thus, steroid regulation of GnRH synthesis and secretion can be direct, but the predominant effects are transmitted through steroid-responsive neuronal systems in various parts of the brain. There is also emerging evidence of direct effects on GnRH cells. Overriding effects on synthesis and secretion of GnRH can be observed during aging, in undernutrition and under stressful situations; these involve various neuronal systems, which may have serial or parallel effects on GnRH cells. The effect of aging is accompanied by changes in GnRH synthesis, but comprehensive studies of synthesis during undernutrition and stress are less well documented. Altered GnRH and gonadotropin secretion that occurs in seasonal breeding animals and during the pubertal transition is not generally accompanied by changes in GnRH synthesis. Secretion of GnRH from the brain is a reflection of the inherent function of GnRH cells and the inputs that integrate all of the central regulatory elements. Ultimately, the pattern of secretion dictates the reproductive status of the organism. In order to fully understand the central mechanisms that control reproduction, more extensive studies are required on the neuronal circuitry that provides input to GnRH cells.     

Synthesis and Antiproliferative Activity of Some New Coumarin Derivatives Derived from 8-Hydroxycoumarin

Russian Journal of Bioorganic Chemistry - A new series of coumarin-derived molecules have been synthesized and evaluated for their anticancer activity against human hepatocellular liver carcinoma...     

Cysteine Racemization in Peptide Synthesis: A New and Easy Detection Method

A new method has been developed for the rapid determination of D-cysteine contents in synthetic peptides. It is based on the reduction of cystine residues, when present, with tris- alkylphosphines, selective derivatization of the cysteine residues with 4-vinylpyridine, followed by acid hydrolysis of the (4-pyridylethyl)cysteine –peptides. Baseline enantiomeric resolution of theD ,L -S-β-(4-pyridylethyl)cysteine, and thus quantification ofD - enantiomer contents at levels ≤1%, is easily achieved by capillary zone electrophoresis exploiting the host–guest complexation principle with crown ethers or by gas chromatography on chiral glass capillary columns upon conventional derivatization of the hydrolysate. The acid-stability of the (4-pyridylethyl)cysteine derivative prevents racemization via thiazoline intermediates and allows for standardization of the acid hydrolysis-dependent racemization.     

An Efficient,Optimized Synthesis of Fentanyl and Related Analogs

The alternate and optimized syntheses of the parent opioid fentanyl and its analogs are described. The routes presented exhibit high-yielding transformations leading to these powerful analgesics after optimization studies were carried out for each synthetic step. The general three-step strategy produced a panel of four fentanyls in excellent yields (73–78%) along with their more commonly encountered hydrochloride and citric acid salts. The following strategy offers the opportunity for the gram-scale, efficient production of this interesting class of opioid alkaloids.     

Sustained Liver Targeting and Improved Antiproliferative Effect of Doxorubicin Liposomes Modified with Galactosylated Lipid and PEG-Lipid

In this study, a cleavable PEG-lipid (methoxypolyethyleneglycol 2000-cholesteryl hemisuccinate, PEG₂₀₀₀-CHEMS) linked via ester bond and galactosylated lipid ((5-cholesten-3β-yl) 4-oxo-4-[2-(lactobionyl amido) ethylamido] butanoate, CHS-ED-LA) were used to modify doxorubicin (DOX) liposome. DOX was encapsulated into conventional liposomes (CL), galactosylated liposomes (modified with CHS-ED-LA, GalL), pegylated liposomes (modified with PEG₂₀₀₀-CHEMS, PEG-CL), and pegylated galactosylated liposomes (modified with CHS-ED-LA and PEG₂₀₀₀-CHEMS, PEG-GalL) using an ammonium sulfate gradient loading method and then intravenously injected to normal mice. Both PEG-GalL DOX and GalL DOX gave relatively high overall drug targeting efficiencies to liver ((T _e)_liver) and were mainly taken up by hepatocyte. However, PEG-GalL DOX showed unique “sustained targeting” characterized by slowed transfer of DOX to liver and reduced peak concentrations in the liver. The biodistribution and antitumor efficacy of various DOX preparations were studied in hepatocarcinoma 22 (H22) tumor-bearing mice. The inhibitory rate of PEG-GalL DOX to H22 tumors was up to 94%, significantly higher than that of PEG-CL DOX, GalL DOX, CL DOX, and free DOX, although the tumor distribution of DOX revealed no difference between PEG-GalL DOX and PEG-CL DOX. Meanwhile, the gradual increase in the liver DOX concentration due to the sustained uptake of PEG-GalL DOX formulations resulted in lower damage to liver. In conclusion, the present investigation indicated that double modification of liposomes with PEG₂₀₀₀-CHEMS, and CHS-ED-LA represents a potentially advantageous strategy in the therapy of liver cancers or other liver diseases.     

Synthesis of Analogs of Pestalotin

Starch-utilizing mutants of Escherichia coli which can grow well on starch or amylose as the sole carbon source were isolated. The maximal viable cell number of the starch-utilizing mutants on the polysaccharide media reached the same level (4 × 10⁹ cells/ml) as that with glucose medium after incubation for 24 hours at 37°C. The isolated mutants could produce more intracellular α-amylase than the wild-type strain, and the enzyme activity was detected in the extracellular fluid. Polyacrylamide gel electrophoresis showed that the intracellular and extracellular enzymes had similar electrophoretic mobilities. These observations suggested that the ability of growth on the polysaccharide media was due to the excreted α-amylase, which appeared to be identical with the intracellular enzyme.     

New Combretastatin Analogs as Anticancer Agents: Design,Synthesis, Microtubules Polymerization Inhibition,and Molecular Docking Studies

A new series of 4-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives were synthesized as analogs for the anticancer drug combretastatin A-4 ( CA-4 ) and characterized using FT-IR, ¹H-NMR, ¹³CNMR, and HR-MS techniques. The new CA-4 analogs were designed to meet the structural requirements of the highest expected anticancer activity of CA-4 analogs by maintaining ring A 3,4,5-trimethoxyphenyl moiety, and at the same time varying the substituents effect of the triazole moiety (ring B ). In silico analysis indicated that compound 3 has higher total energy and dipole moment than colchicine and the other analogs, and it has excellent distribution of electron density and is more stable, resulting in an increased binding affinity during tubulin inhibition. Additionally, compound 3 was found to interact with three apoptotic markers, namely p53, Bcl-2, and caspase 3. Compound 3 showed strong similarity to colchicine , and it has excellent pharmacokinetics properties and a good dynamic profile. The in vitro anti-proliferation studies showed that compound 3 is the most cytotoxic CA-4 analog against cancer cells (IC₅₀ of 6.35 μM against Hep G2 hepatocarcinoma cells), and based on its selectivity index (4.7), compound 3 is a cancer cytotoxic-selective agent. As expected and similar to colchicine , compound 3 -treated Hep G2 hepatocarcinoma cells were arrested at the G2/M phase resulting in induction of apoptosis. Compound 3 tubulin polymerization IC₅₀ (9.50 μM) and effect on V_max of tubulin polymerization was comparable to that of colchicine (5.49 μM). Taken together, the findings of the current study suggest that compound 3 , through its binding to the colchicine-binding site at β-tubulin, is a promising microtubule-disrupting agent with excellent potential to be used as cancer therapeutic agent.     

Synthesis and Antiviral (RNA) Evaluation of Nucleoside Analogs of Tiazofurin Modified at the Carboxamide Moiety

Abstract

The carboxamide functionality of tiazofurin 1a has been modified to produce the following analogs: carboximidates 5a,b, carboxamidines 6, 10, tetrahydropyrimidine 7, N-glycine 8 and N-glutamine 9. These structural modifications abolished the in vitro antiviral (RNA) activity exhibited by tiazofurin against the flaviviruses (yellow fever and Japanese encephalitis viruses), bunyavirus (Punta Toro virus) and togavirus (Venezuelan equine encephalomyelitis virus). Only carboximidates 5a,b retained marginal activity against bunyaviruses.     

Design,Synthesis, and Antimycobacterial Evaluation of Novel Tetrahydroisoquinoline Hydrazide Analogs

A series of novel 2-substituted-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carbohydrazide were designed, synthesized and structures were confirmed by analytical methods, viz., ¹H-NMR, ¹³C-NMR and Mass spectrometry. Synthesized derivatives were evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Ra. Among all the evaluated compounds, 10A25 containing biphenyl moiety exhibited significant inhibition with IC₅₀ 4.7 μM. 10A19 , with an electron-withdrawing Iodo group in the ortho position of the phenyl exhibited significant anti-tubercular activity with IC₅₀ 8.8 μM. IC₅₀ values of the remaining compounds ranged from 9.2 to 73.6 μM. Molecular docking study of the significantly active compound 10A25 was performed to determine the putative binding position of the test ligand at the active site of the selected target proteins Mycobacterium tuberculosis enoyl reductase (InhA) PDB – 4TZK and peptide deformylase PDB – 3E3U. A suitable single crystal for one of the active compounds, 10A12 , was generated and analysed to further confirm the structure of the compounds.     

A First Microwave-Assisted Synthesis of a New Class of Purine and Guanine Thioglycoside Analogs

A first microwave-assisted synthesis of a new class of novel purine thioglycoside analogs from readily available starting materials has been described. The key step of this protocol is the formation of sodium pyrazolo[1,5-a]pyrimidine-7-thiolate and 7-mercaptopyrazolo[1,5-a]pyrimidine derivatives via condensation of 5-amino-1H-pyrazoles with sodium 2,2-dicyanoethene-1,1-bis(thiolate) salts or 2-(dimercaptomethylene)malononitrile, respectively, under microwave irradiation, followed by coupling with halo sugars to give the corresponding purine thioglycoside analogs. The obtained purines and purines thioglycosides derivatives were evaluated in vitro against lung (A549), colon (HCT116), liver (HEPG2), and prostate (PC3) cancer cell lines. Some of these compounds (5b, 5d, 5f, and 9a–d) exhibited little potency toward the four cell lines. On the other hand, compound 5a elicited higher cytotoxicity on both prostate (PC3) and colon (HCT116), respectively, while it was found moderate on lung (A549), and inactive on liver (HEPG2). Moreover, compound 5c was found moderate with LC₅₀ values 52.0–88.9 μM for almost all the cell lines.