Microwave Assisted Synthesis of Novel Six-Membered 4-C, 4-O and 4-S Lactams Derivatives: Characterization and in vitro Biological Evaluation of Cytotoxicity and Anticoagulant Activity

Abstract

A series of six-membered lactam derivatives containing C, O and S atoms in position 4 were synthesized using microwave methodology through coupling reactions. The novel compounds were synthesized following two step reaction to yield fifteen derivatives. The final derivative N-(4-(3-oxotiomorpholin)phenyl) hexanamide was selectively toxic to the HCT-116 cell line over the HeLa cancerous and HEK-293 human non-malignant control cells with low inhibition Factor Xa (FXa) activity. The new products were characterized by spectral data including 1 H and 13 C nuclear magnetic resonance (NMR), infrared (IR) and high-resolution mass spectrometry (HRMS). Cytotoxicity of products on HCT-116, HeLa, HEK-293 cell lines and FXa activity assays are also reported. Keywords: lactam derivatives, microwave, coupling reactions, cytotoxic activity, FXa activity IntroductionAccording to statistics from the World Health Organization (WHO), 1 the mortality rate associated with age-standardized cancer was 115.3 per 100,000 inhabitants in 2012. The analysis reported by the Department of Health Statistics and Information (DEIS), which is a department within the Chilean Health Ministry (MINSAL), reported that colon cancer was the cause of 1,410 deaths. This finding corresponds to a mortality rate of 8.2 per 1,000 people in 2012.2 This epidemiologic data supports the pressing need for on-going research to find novel compounds for the treatment of colon cancer.Indeed, existing data from basic cancer research shows that the haemostatic components and the cancer biology are interlinked in multiple ways.3 Nonetheless, it is noteworthy that while a group of cancer cells is capable of activating the clotting system, haemostatic factors play a role in tumor progression. 4 Moreover, current antineoplastic drugs are useless due to their high toxicity, side effects and low selectivity. Thus, novel scaffolds for the development of antineoplastic drugs has become a rapidly growing field of scientific interest, and highlight the development of small molecules with activity involving lactam moieties. Usually, reported protocols for synthesizing these interesting kinds of structures require multiple-step synthesis, long reaction times and high temperatures which ultimately results in low yields of the desired products. In this context, our research group is focused on the synthesis of new 4-C, 4-O and 4-S lactams with an aromatic amide substituent by means of using microwave assisted methodologies in order to diminish reaction time and increase the yield of the product. In this research, a modified Ullmann type reaction, using microwave approach and peptide coupling methods 7 was performed to provide a new group of interesting compounds with enhanced Microwave Assisted Synthesis of Novel Six-Membered 4-C, 4-O and 4-S Lactams Derivatives J. Braz. Chem. Soc. 204 selective cytotoxic activity for neoplastic cells HCT-116 (human colon cancer).The chemical structure of these newly synthesized molecules has a similar main core of Factor Xa (FXa) commercially av...

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

“…In a theoretical study of C-arylations with aryl halides [79], the authors have explained the reaction reactivity between the corresponding lactams and 4-iodoaniline compound [67]. According to this, the reaction conditions were optimized by using lactam 1 (1.2 equivalents), aniline 5 (1 equivalent), CuI as catalyst and N,N'-dimethylethylenediamine (DMEDA) as ligand, in toluene as solvent using different heating sources ( Table 2).…”

“…Moreover, these methodologies are therefore being used as an important synthetic tool [59][60][61][62][63]. For these reasons, our group has been interested in using microwave approaches to achieve our synthetic goals [64][65][66][67] in the last few years.…”

“…To this end, we have reported a modified Ullmann type procedure for related main core structures using microwave-assisted methodologies [67]. Currently, the utilization of microwave-assisted methodologies allows for the desired organic molecules in only three steps to be reached which involves Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions.…”

A link between cytotoxicity in cell culture and gastrointestinal side effects of oral anticoagulants: bench-to-bedside

“…Dabigatran-related dyspeptic symptoms have been suggested to result from the hyperacidic microenvironment on the surface of gastric mucosa formed by the tartaric acid within the galenic formation to increase the absorption, but not from the cytotoxic effects of the drug (20). Also, several studies using rivaroxaban, apixaban, warfarin and warfarin-derivatives have demonstrated that these drugs prevent cellular proliferation and migration in certain cell lines and show anti-tumorigenic or apoptotic effect at certain doses (21,22,23). However, there is no study in the literature which investigates the direct cytotoxic effects of these drugs.…”

Theoretical investigation into the coordination of R‐/S‐asymmetric uranyl–salophens containing six‐membered ring lactam with cis−/trans‐cyclohexylamines

“…As one of the most important cyclic organic compounds, lactam can form a variety of configurations of the ring structure and widely exists in many natural products and synthetic compounds and is often used in pharmaceutical and bioactive molecules . The green synthesis of chiral compounds containing lactam has become one of the hotspots in the field, especially chiral molecules with six‐membered ring lactams because they are found to have good coordination selectivity, biological activity, and so on .…”