Letters in Organic Chemistry - Volume 13, Issue 9, 2016

Background: Instability of the macrolide, high toxicity and water insolubility of epothilone B derivatives limit their application as clinical injectable drugs. For example, PEGlated epothilone B was reported to ameliorate its water solubility and stability, and cyclodextrins polymer (CDP) was also used to drug delivery of epothilones. However, ectogenic polymers may cause lots of potential adverse reactions because of incompatibility with human body. Glutathione, a water-soluble endogenous tripeptide, plays an important role in the biological systems and involves multiple cellular functions, which seems to be a preferred compound for drug delivery. Thus, this paper report here the synthesis and evaluation of glutathione-epothilone B. Methods: Derivatization of epothilone B at 3-hydroxyl group and 7-hydroxyl group by coupling with a lincker, α-iodoacetic acid, generated a epothilone B-iodoacetic acid derivative, which reacted with glutathilone to give glutathione-epothilone B. The water-solubility of the conjugate was measured. And the in vitro inhibitory activity to cancer cells and toxicity of the conjugate was evaluated by MTT assay. The stability of the conjugate in phosphate buffer saline and in human serum was studied, respectively, to support the results of the in vitro evaluation. Results: The solubility in water of the conjugate, glutathione-epothilone B, was remarkably improved to at least 4000 times greater than that of epothilone B. According to the results of the in vitro evaluation, the conjugate exhibited potent inhibitory activity to human liver cancer cells (HepG2 cells), which was slightly more potent than the lead compound epothilone B. Meanwhile, the toxicity of the conjugate was much lower than that of epothilone B. Releasing epothilone B of the conjugate was observed in human serum, which was completed in about 8 hours. And the conjuate was more stable in the pH 7.4 phosphate buffer saline. We believed that the introduction of glutathione can not only increase the stability of epothilone B, but also lead to reduced toxicity. Conclusion: This paper reported that the successful synthesis of a more stable and water-soluble prodrug of epothilone B, glutathione-epothilone B, which exhibited better inhibitory activity to human liver cancer cells (HepG2 cells). Moreover, the reported conjugate showed much lower toxicity to primary human hepatocyte than epothilone B.

Background: Calixarenes are well-known building blocks in supramolecular chemistry. Introduction of the halogen atom at the upper rim of the molecule allows to obtain very promising synthons for synthesis of more complex calixarene structures. Each halogen is specific for the certain types of reactions. It is known that chlorine derivatives are preferable for the Kumada, Hiyama, Stille, Negishi, Suzuki cross-coupling reaction and Buchwald-Hartwig amination. para-Сhlorinated derivatives of calix[4]arene were described in the literature even less than other halogenated ones because of their synthesis complication (low yield construction from chlorophenols). Methods: To increase the yield of p-chlorinated calix[4]arene and to reduce the number of synthetic steps ipso-chlorination reactions were tried. Reactions were carried out in dry tetrachloromethane with sulfuryl chloride in the presence of Lewis acids (AlCl3, FeCl3, PCl5). Results: It was shown that PCl5 presence led to the best yield (57%). It was almost two times higher than in the case of aluminum chloride use. Unfortunately, the reaction with FeCl3 did not give the individual product. Conclusion: A new method for synthesis of dichlorinated at the upper rim calix[4]arenes via ipsochlorination with sulfuryl chloride in the presence of phosphorous pentachloride was developed. The influence of other Lewis acids was studied. The number and position of chlorine atoms in the structure of obtained compounds were confirmed.

Background: In recent years, an increasing interest has been focused on the synthesis of 2-substituted 1,3-indandione compounds owing to their significant biological activity. It is well known that indandione and related compounds exhibit a wide range of biological activities such as antitumor, anticancer, sedative, hypotensive and neuromuscular blocking activities. The synthesis of various 2-substituted-1,3-indandiones has initially been stimulated by their known anticoagulant and pharmacological properties. As a very strong electron acceptor, 1,3-indandione is a part in new dipolar molecules exhibiting interesting optical properties and used as dopants in novel functional materials. Methods: A mixture containing aldehyde, 1,3-indandione, indole and [BDBDIm]Br were heated at 80°C for the required reaction times. The progress of the reaction was monitored by TLC (EtOAc: petroleum ether 1:3). After completion of the reaction, the product was extracted with CHCl3/H2O and preferred the organic phase. After evaporation and recrystallization, the pure product was obtained. The aqueous phase was evaporated also to produce recycled bis ionic liquid [BDBDIm]Br. The identity and purity of the products were confirmed by IR, 1H NMR, 13C NMR and elemental analysis. Results: In continuation of our ongoing studies to synthesize of heterocyclic and pharmaceutical compounds at mild and practical protocols, herein we wish to report our experimental results on the synthesis of new generation of 1,3-indandione using various aromatic aldehydes, indole, 1,3-indandione in the presence of novel bis ionic liquid ([BDBDIm]Br) and the results were listed. After reaction, the bis ionic liquid is easily separated from the reaction medium by washing with distilled water (IL is soluble in water). The washed bis ionic liquid is distilled under vacuum to recover solvent for reuse in subsequent reactions. Our experiments also indicated that after six runs, the catalytic activities of the reagents were almost the same as those of fresh catalysts Conclusion: Finally, we develop an efficient and convenient procedure for the synthesis of 1,3- indandiones through three component synthesis of aldehydes, indole and 1,3-indandione catalyzed by [BDBDIm]Br as a reusable ionic liquid as catalyst. The remarkable advantages offered by this method are: catalyst is inexpensive, non-toxic, easy handling and reusable, simple work-up procedure, short reaction time, high yields of product with better purity and green aspect by avoiding toxic catalyst and hazardous solvent. Apart from the mild conditions of the process and its excellent results, the simplicity of product isolation and the possibility to recycle the catalyst offer a significant advantage. To the best of our knowledge this is the first report on synthesis of 1,3-indandiones using ionic liquid 3, 3-(butane- 1,4-diyl) bis (1,2-dimethyl-1H-imidazole-3-ium) bromide.

Background: Carbo(thio)amid derivatives 4a, 4b were obtained starting from nalidixic acid in three steps. The acidic treatment of compound 4a generated the corresponding 1,3,4-oxadiazole (5), while the compound 4a gave 1,2,4-triazole derivatives 8a, 8b in basic media. The condensation of 4a with ethyl bromoacetate and 4-chlorophenacyl bromide afforded 1,3-oxazolidine, 6 and 1,3-thiazolidine, 7 derivatives. The synthesis of Mannich bases of 9-15 and 17-19 were achieved from the reaction of 1,2,4- triazoles, 8a, 8b and 1,3,4-oxadiazole, 16, with several heterocyclic amines that has biological activity. Methods: In this article, a series of triazole or 1,3,4-oxadiazole rings containing some novel biologically active quinolone derivatives. Conventional and microwave assisted methods were used for all syntheses. Moreover, the effect of acid catalyst on Mannich reactions was investigated. The structures of newly synthesized compounds were elucidated on the basis of 1H NMR, 13C NMR, FT IR, EI MS techniques and elemental analysis. All these compounds were screened in vitro for their antimicrobial activity against various gram-positive and gram-negative bacterial and fungal strains. Results: This study reports the successful synthesis of some new hybrid compounds starting from nalidixic acid. Two methods containing conventional and microwave assistance with/without catalyst were used to obtain the target compounds. Microwave assistance supplied more efficient way leading the formation of target compounds. Moreover, the effect of acid catalyst on Mannich reactions was investigated. The antimicrobial activity screening studies were also performed in the study. Conclusion: The antimicrobial screening suggests that the compounds containing norfloxacin (9a,b and 17), ciprofloxacin (10a,b and 18) or 7-aminocephalosporanic (12) acid nucleus displayed excellent antimicrobial activity. Moreover, some of them (5-7, 8-13, 15-18) displayed inhibition properties on Escherichia coli (Ec) and Mycobacterium smegmatis (Ms) better from ampicillin or streptomycin with the mic value 0.24 μg/mL.

Background: A one-pot method for the preparation of the corresponding alkoxy acetic acids by low-temperature ozonolysis of allyl ethers/esters followed by treatment with semicarbazide hydrochloride has been suggested. The reaction occurs via formation of acetoxyhydroperoxide, subsequent reduction of which depends on the process temperature and the nature of the starting substrate. Objective: The article is aimed at the development of one-pot method for obtaining practically important alkoxy acetic acids, because the ozonolytic cleavage of a С=С double bond is the key step in full syntheses of many biologically active compounds. Methods: We used a low temperature ozonolysis of functionally substituted olefins in the system acetic acid-methylene dichloride followed by reduction of semicarbazide hydrochloride. To create a method we have used available allyl ethers/esters as starting materials. Results: We investigated reaction of the peroxide products of ozonolysis of monoallyl ethers, ester and diallyl ethers in an Ц#144;#129;Ц#158;Ц#157;/CH2Cl2 mixture on treatment with semicarbazide hydrochloride at various temperatures. We have discovered that the selectivity of reduction of acetoxyhydroperoxide formed at the first stage depends both on the process temperature and on the nature of the starting substrate. A decrease in temperature favors acid hydrolysis and formation of a carboxylic acid. Conclusion: We have proposed a simple and highly efficient one-pot method for the preparation alkoxy acetic acids without isolation of intermediate peroxides.

Background: Phthalides are pervasive benzolactone structural frameworks in nature and have a broad profile of biological activities. Catalytic asymmetric reduction with the in situ lactonization of 2-acylarylcarboxylate compounds is an efficient strategy for chiral phthalide synthesis. The tartaric acid-derived reagent TarB–X is capable of mediating the asymmetric reduction of aromatic ketones using either LiBH4 or NaBH4 as the reductant. Up until now, the asymmetric reduction by Tarb- H/NaBH4 had not been applied to the synthesis of chiral phthalides. Methods: The requsite substrate, methyl 2-acetylbenzoate was obtained by a two step reaction starting from phthalic anhydride and maloninc acid. Tarb-H was obtained by treatment of L-(+)-tartaric acid with phenylboronic acid. The catalyst and NaBH4 were reacted with methyl 2-acetylbenzoate at room temperature for 1 h. The structure of (R)-3-Methylphthalide was established by NMR and mass spectrometry and its enantiomeric excess was determined by HPLC. The relative configuration was deduced by comparison of the optical rotation with data given in the literature. Results: (R)-3-Methylphthalide was obtained in moderte yield and high enantiomeric excess. Conclusion: (R)-3-methylphthalide was prepared in high enantiomeric excesses using an inexpensive and easily synthesized tartaric acid derived boronic ester (TarB–H) with sodium borohydride. The chiral phthalide was obtained in an open flask by reductive cyclization of a 2-acylarylcarboxylate.

Background: In the present study, a series of 5,7-disubstituted-2-phenyl-5H-[1,3,4] thiadiazolo[3,2-a]pyrimidine derivatives have been reported. The title compounds were synthesized by the reaction of substituted chalcones with 5-phenyl-1,3,4-thiadiazol-2-amine in n-butanol. Methods: All reactions were performed at reflux temperature and the synthesized compounds were characterized by IR, NMR and Mass spectroscopic techniques. Results: The synthesized compounds were screened for their antimicrobial and antioxidant activities. The compounds displayed significant antimicrobial and antioxidant activities. Additionally, the selected compounds were screened for in silico molecular docking studies. Conclusion: In the present work, we have reported an efficient method for the synthesis of some new 5,7-disubstituted-2-phenyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine derivatives. Collectively, all the current computational insights support the in vitro observations seen for antimicrobial and antioxidant agents. Further, the pyrimidine derivatives might act as potential specific inhibitors of G6P synthase thereby facilitating its biological activities. From the activity results, it has been concluded that among the studied compounds, compounds 5b, 5d, 5e, 5g, 5i, 5m and 5n could serve as potential antimicrobial and antioxidant agents.

Background: The synthesis of effective drugs are very important for the scientist. The various biological effects of the thiazole, oxime and ether functional groups are well known properties by the drug developers. So we have synthesised new molecules which contains three of them on the same molecules. Methods: The acetophenone derivatives have been used for synthesis new oximes. The synthetic pathway includes mainly four steps. s1. α-Bromination of acetophenone derivatives, s2. Synthesis of thiazole ring using brominated acetophenones, s3. Synthesis of ethers using synthesised thiazole, s4. Synthesis of oximes. Results: The synthesised molecules characterised using IR,1H-NMR, 13C-NMR and elementel analysis methods. Conclusion: The new oximes which include thiazole and ether groups have been synthesised using acetophenone derivatives.

Background: For lost twenty years, Agomelatine, a melatonin-like antidepressant drug which is based on a naphthalene moiety has received a huge attention. This drug molecule gets short plasma half-life as a result of undergoing very important liver first pass effect. So in order to overcome this drawback, we have come up with an approach which is based on the use of substituted aryl derivatives of tetrazole scaffold to replacement of the N-acetyl side chain. We successfully designed aryl substituted tetrazolo naphthalene 3(a-f) scaffolds, a much centered template which can be elaborated further into agomelatine compounds. Methods: The compound which is used in the present scheme as starting material, that is, 2-(7- methoxynaphth-1-yl)acetonitrile 1 react with NaN3 in the presence of NH4Cl as a catalyst in dimethyl formamide as solvent to provide the corresponding 5-(7-Methoxynaphth-1-yl methyl)-1H-tetrazole 2, which on reaction with aryl halides a-f in presence of K2CO3 yielded the corresponding N-substituted tetrazolonaphthalenes 3(a–f). Results: Novel analogues of agomelatine 3(a-f) were synthesized from 2-(7-methoxynaphth-1- yl)acetonitrile 1. The newly synthesized compounds were established by Infra Red, 1H, 13C Nuclear Magnetic Resonance, mass spectroscopy and the data of their elemental analyses. Conclusion: We developed a simple and efficient method for the synthesis of aryl substituted tetrazolo naphthalene 3(a-f) scaffolds, a much centered template which can be elaborated further into agomelatine compounds. Along with this work, further important works are under progress to get more biological activity results.

Background: Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death. Cancer is caused by inherited genetic mutations, hormones, and immune conditions. These factors may act together or in sequence to cause cancer. Ten or more years often pass between exposure to external factors and detectable cancer. Worldwide, one in seven deaths is due to cancer; cancer causes more deaths than AIDS, tuberculosis, and malaria combined. Chemotherapy was one of the important techniques for the treatment of cancer by using several chemotherapeutic agents. It involves the use of cytotoxic agents that destroy rapidly dividing cells. Despite of this progress, the discovery of most potent anti-cancer agents is a challenging issue in cancer chemotherapy without any side effects for the future generations. Methods: The anticancer activity of the compounds was determined using MTT (3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) reduction assay. The molecular docking studies were performed using the Discovery Studio (DSv2.5) and GOLD installed in Window7. The X ray crystallographic structure of tubulin with colchicines as reference ligand (PDB: 1SA0) at resolution 3.58 Å with r value 0.233 (obs.) was downloaded from the protein data bank (PDB). Results: Among the synthesized compounds, the compounds 10f, 10g, 10h, 10i and 10j showed more potent activity than control. The compound 10f, 10i and 10j showed comparatively higher anticancer activity than the standard (E7010) on all the three cell lines, while compound 10g and 10h showed higher activity than the standard (E7010) on ACHN and A549 cancer cell lines respectively. The order of anticancer activity of was found to be 10i > 10f > 10j > E7010. The current docking studies clearly presented the binding modes of the compounds in the active site of the colchicine binding site of the tubulin receptor. Conclusion: The synthesis of novel pyridine based chalcones (10a-10j) was performed. All the compounds were completely characterized by spectroscopic data and elemental analysis. All these synthesized compounds were evaluated for anticancer potential against three human cancer cell lines (ACHN, MCF-7 and A-549). Among them compounds 10f, 10g, 10h, 10i and 10j were showed more potent activity than control drug.

Background: Homo and hetero dimers of macrodilacto cyclic compounds were observed frequently in nature and they were built with different types of functional groups, chemical skeletons and ring sizes. Natural products with macrodiolide frameworks are also known to exhibit a wide range of biological properties including antibiotic, antifungal, antihelmintic, phytotoxic, and antileukemic activities. The main aim of this paper was the stereoselective total synthesis of (-)-Pyrenophorin from commercially available starting material (S)-propylene oxide with high yields. Methods: Stereoselective total synthesis of (-)-Pyrenophorin was done by hydrolytic kinetic resolution, Wittig olefination followed by Mitsunobu reaction. Results: The disconnection approach analysis (retrosynthetic) of (-)-Pyrenophorin envisions that it would be synthesized through the hydroxyl-acid via cyclo dimerisation under the Mitsunobu reaction conditions and followed by deprotection of cyclic ketals. Hydroxy-acid would be achieved from alcohol, while the alcohol would be obtained from (S)-propylene oxide. Conclusion: The total synthesis of target molecules achieved from commercially available starting materials, soft reaction conditions, decrease of reaction conditions and high purities with large yields. These type of biologically potent target molecules total synthesis was very important in industrial point of view.