HETEROCYCLES

■ Contents

■ Synthesis of Elastin Crosslinker Desmosines

Hiroaki Tanaka and Toyonobu Usuki*

*Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan

Abstract

Desmosine (1) and isodesmosine (2) are 1,3,4,5- and 1,2,3,5-tetrasubstituted pyridiniums and exist only in the extracellular matrix protein elastin as major crosslinking amino acids. They are formed by the condensation and cyclization of one lysine and three allysines, generated from lysine by lysyl oxidase. Since the discovery of desmosines in 1964, there have been no reports on their chemical synthesis for decades. The first total synthesis of 1 was reported in 2012 and since then, isodesmosine (2), desmopyridine (3), isodesmopyridine (4), neodesmosine (5), and merodesmosine (6) have been synthesized. Isotopically labeled desmosines have also been synthesized for the precise analysis of desmosines using isotope-dilution LC–MS/MS analysis. Synthesis of conjugates with desmosines and carrier proteins was achieved for antibody production. This review summarizes a series of desmosine syntheses based on cross-coupling reactions and Chichibabin pyridinium synthesis as synthesis methodologies. The obtained results would help in the development of novel diagnostic and therapeutic methodologies for elastin-degradation-related diseases.

■ Construction of Supramolecular Frameworks Comprised of Fully-Substituted Cyclopentanocucurbit[6]uril and Two Phenolic Acids

Naqin Yang, Yue Ma, Jun Zheng, Xinan Yang, and Peihua Ma*

*Key Laboratory of Macrocyclic and Supramolecular Chemistry of Guizhou Province, Guizhou University, Guiyang 550025, People’s Republic of China

Abstract

In this paper, fully substituted cyclopentanocucurbit[6]uril (CyP6Q[6]) and calcium ions were coordinated in the presence of cadmium chloride in hydrochloric acid solution, followed by the addition of p-hydroxybenzoic acid (G1) and 2,5-dihydroxybenzoic acid (G2) to construct two supramolecular frameworks, respectively. Their structures and interactions were characterized using single-crystal X-ray diffraction, X-ray powder diffraction. The results showed that calcium ions coordinate with the carbonyl-fringed portals of CyP6Q[6], G1 and G2 act on the outer surface of CyP6Q[6] via C-H....π interactions, and [CdCl4]2– participates in ion-dipole interactions with CyP6Q[6] to form a framework structure consisting of pores and layers.

■ Synthesis, Chracterization and Insecticidal Evaluation of Some p-tert-Butylthiacalix[4]arene Derivatives against Cowpea Aphid (Aphis craccivora Koch)

Omran A. Omran,* Amer A. Amer, Ali M. Drar, Igor S. Antipin, and Ayman Nafady*

*Chemistry Department, Faculty of Science, Sohag University, 82524, Sohag, Egypt

Abstract

Herein, we offer a facile synthesis of three novel conformers (cone, partial cone, and 1,3-alternate) of thiacalix[4]arene derivatives, comprising 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetrakis{2-oxo-2-[(dimethylamino-methylidene)hydrazino]ethoxy}-2,8,14,20-tetrathiacalix[4]arene, 3a-c via the thiocarbonylation of their corresponding carbonyl derivatives 2a-c with Lawesson’s reagent (LR) in refluxed chloroform with good yields (80, 95, and 85%, respectively). The new O/S exchanged tetrathiacalix[4]arene products (3a-c) were identified by various spectroscopic tools such as FT-IR, 1H NMR, and 13C NMR. Importantly, agrochemical efficacy of the as-prepared thionated p-tert-butylthiacalix[4]arene conformers (3a-c) as well as the parent derivatives 2a-c were investigated against adults and nymphs of Cowpea aphid (Aphis craccivora). In view of the calculated IC50 values, conformers 2c and 3c possessed the highest insecticidal potency, with respective values of 5.47 and 3.50 ppm against nymphs, whereas values of 14.38 and 14.04 ppm were recorded against Cowpea aphid adults. The overall finding of this work may give an inspiration and motivation on the search for new eco-friendly insecticidal agents that have strong toxicological potency but with minimal impact on the environment.

■ Design, Synthesis, and Biological Evaluation of Novel 6,8-Disubstituted Imidazo[1,2-a]pyridine Derivatives as a CDK2 Inhibitors

Bhargav Bhimani, Ashish Patel,* Umang Shah, Afzal Nagani, Vruti Parikh, Harnisha Patel, Hirak Shah, Drashti Shah, Bhavna Patel, and Nilesh Pandey

*Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT Campus, Changa-388421, India

Abstract

Imidazo[1,2-a]pyridine exerts a notable pharmacological efficiency and has emerged as an integral backbone for the treatment of various cancer. Inhibition of cyclin-dependent kinases has emerged as a potential therapeutic strategy for a variety of cancers. Here, we discuss the synthesis of imidazo[1,2-a]pyridine derivatives modified at positions 6 and 8 prepared using Suzuki-Miyaura cross-coupling, Buchwald reaction, and peptide coupling as the main synthetic methods. All synthesized compounds were characterized by spectroscopy techniques after purification and screened for their anti-cancer activity by in vitro MTT assays against MCF-T cell line and CDK2 inhibition by kinase inhibition assay. The in vitro and kinase inhibition assay revealed that compounds 11ii, 11iii, 11xxi, 11vi, and 11viii show potent anti-cancer activity for the treatment of breast cancer. This study demonstrates that substituted imidazo[1,2-a]pyridine can be exploited for future cyclin-dependent kinase (CDK2) inhibitor development.

■ Cysteine Catalyzed Water Mediated Eco-Friendly Approach for the Synthesis of 5-Substituted 1H-Tetrazole and Its Derivatives

Vikas V. Borge, Ramchandra G. Thorat, Arun K. Kadu, Vikas M. Bangade, Parag S. Panse, Gangadhar A. Meshram, and Bhushan B. Popatkar*

*Department of Chemistry, University of Mumbai, Vidyanagari, Kalina, Santacruz (E), Mumbai, Maharashtra 400 098, India

Abstract

Cysteine catalyzed, water mediated, one-pot multi-component protocol for the synthesis of 5-substituted 1H-tetrazole and its functional derivatives has been developed. The reaction between various aldehydes, hydroxylamine hydrochloride and sodium azide under the optimized reaction condition affords desired product(s). The utilization of water as a green solvent for the synthesis of the titled compounds is an important feature of this process. The moderate to high yield of the product, reaction at room temperature, exclusion of volatile toxic organic solvent and an operational simplicity are some of the advantages of this methodology.

■ Synthesis of Arylideneisoxazol-5-ones Catalyzed by Sodium Cyclamate

Ziba Daroughezadeh and Hamzeh Kiyani*

*School of Chemistry, Damghan University, 36719-41167 Damghan, Iran

Abstract

The three-component reactions using aryl aldehydes, hydroxylamine hydrochloride, and β-ketoesters (ethyl acetoacetate, ethyl 4-chloro-3-oxobutanoate, and ethyl 3-oxohexanoate) as available precursors were performed to synthesize arylideneisoxazol-5-ones. The experiments have been catalyzed using sodium cyclamate and high yields of products were obtained under green conditions at room temperature. Relatively shorter reaction time, free from the use of organic reaction medium, the simplicity of the method, the formation of pure products without using chromatographic methods, and inexpensive are among the advantages of this method. Heating and the use of other devices for energy supply are not required. Also, in this three-component process, using water as a reaction medium is in line with the principles of green chemistry.

■ Stereospecific Skeletal Rearrangement of Epoxides Derived from Methylenecyclobutane-Fused N-Heterocycles

Noriyoshi Arai*

*Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, N13-W8, Sapporo, Hokkaido 060-8628, Japan

Abstract

Irradiation of indole or isocarbostyril derivatives with allenyl side chain under appropriate conditions gave the corresponding methylenecyclobutane-fused N-heterocycles stereoselectively in high yields through intramolecular [2+2] cycloaddition. These addition products could be transformed to ring-expanded compounds without loss of the configuration by using a sequence of epoxidation and skeletal rearrangement.

■ Diterpenoid Alkaloids from Delphinium pachycentrum Hemsl.

Ruijie Lu, YuQi Yang, Shu Wang, Lin Chen, Jiang Xie, Shuai Huang,* and Xianli Zhou*

*School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan, P. R. China

Abstract

Five new C19-diterpenoid alkaloids, named pachycenines A–E (1–5), along with eleven known diterpenoid alkaloids (6–16), were isolated from the whole plant of Delphinium pachycentrum Hemsl. Their structures were elucidated on the basis of comprehensive spectroscopic data analysis, including 1D, 2D NMR, and HR-ESI-MS. Cytotoxicity and anti-inflammatory activity of those compounds were also carried out.