Synthesis and biological evaluation of new fused Isoxazolo[4',5':4,5] pyrano[2,3-d] Pyrimidines as potent anticancer agents

A comprehensive review on pyrazoline based heterocyclic hybrids as potent anticancer agents

The small alkylating molecule, 3-bromopyruvate (3BP), is a potent and specific anticancer agent. 3BP is different in its action from most currently available chemo-drugs. Thus, 3BP targets cancer cells' energy metabolism, both its high glycolysis ("Warburg Effect") and mitochondrial oxidative phosphorylation. This inhibits/ blocks total energy production leading to a depletion of energy reserves. Moreover, 3BP as an "Energy Blocker", is very rapid in killing such cells. This is in sharp contrast to most commonly used anticancer agents that usually take longer to show a noticeable effect. In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells. Therefore, 3BP can be considered a member, perhaps one of the first, of a new class of anticancer agents. Following 3BP's discovery as a novel anticancer agent in vitro in the Year 2000 (Published in Ko et al. Can Lett 173:83-91, 2001), and also as a highly effective and rapid anticancer agent in vivo shortly thereafter (Ko et al. Biochem Biophys Res Commun 324:269-275, 2004), its efficacy as a potent anticancer agent in humans was demonstrated. Here, based on translational research, we report results of a case study in a young adult cancer patient with fibrolamellar hepatocellular carcinoma. Thus, a bench side discovery in the Department of Biological Chemistry at Johns Hopkins University, School of Medicine was taken effectively to bedside treatment at Johann Wolfgang Goethe University Frankfurt/Main Hospital, Germany. The results obtained hold promise for 3BP as a future cancer therapeutic without apparent cyto-toxicity when formulated properly.

Despite the increased success rates of histone deacetylases inhibitors (HDACi) as potent anticancer agents, many metabolic obstacles face the hydroxamic acid-based HDAC inhibitors, which inspired us to develop non-hydroxamate HDAC inhibitors. Based on the established knowledge of the SAR of the reported HDAC inhibitors and based on the knowledge that salicylaldimine moiety is an established chelating agent, a series of salicylaldimine based HDAC inhibitors were designed, synthesized and biologically evaluated. The compound 14 in the present study showed considerable HDAC inhibition and potential antiproliferative activities on NCI cell lines rendering it as a good start for optimization that introduces a new class of non-hydroxamate HDAC inhibitors as potential anticancer agents.

Diarylurea derivatives comprising 2,4-diarylpyrimidines: Discovery of novel potential anticancer agents via combined failed-ligands repurposing and molecular hybridization approaches

Inhibition of histone deacetylase (HDAC) results in growth arrest, differentiation, and apoptosis in nearly all tumor cell lines, promoting HDACs as promising targets for antitumor therapy. In our previous study we developed a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDAC inhibitors (HDACi), among which compound 7d exhibited promising HDAC8 inhibitory and antiproliferative activities. Herein, we report the design and development of a new class of tetrahydroisoquinoline-bearing hydroxamic acid analogues as potential HDACi and anticancer agents. In vitro biological evaluation of these compounds showed improved HDAC8 inhibition (compounds 31a and 31b exhibited mid-nM IC(50) values against HDAC8) and potent growth inhibition in multiple tumor cell lines. Most importantly, compounds 25e, 34a, and 34b exhibited excellent in vivo anticancer activities in a human breast carcinoma (MDA-MB-231) xenograft model compared with suberoylanilide hydroxamic acid (SAHA), an approved HDACi. Collectively, our results indicate that tetrahydroisoquinoline bearing a hydroxamic acid is an excellent template to develop novel HDACi as potential anticancer agents.

Heterocyclic compounds with different heterocycle moieties, namely benzoxazinone, benzimidazole, quinazolinone, and benzofuranone heterocyclic rings, were synthesized, characterized, and evaluated for their anticancer activity against human hepatocellular carcinoma cell line (HepG2) using sulforhodamine B (SRB) and dimethylthiazol‐diphenyltetrazolium bromide (MTT) assays. Also, their cytotoxic activities were tested against human epithelioid carcinoma (Hela) cell line in comparison with normal cell, amniotic epithelial (WISH) cell line, as an in vitro toxicity estimation model. The results showed clearly that 2‐(2‐benzyl‐4‐oxoquinazolin‐3(4H)‐yl)acetohydrazide 4 is the most potent antioxidant and anticancer agents. Although, 3‐amino‐2‐benzylquinazolin‐4(3H)‐one 5 is less potent anticancer agent against Hela but it is more safe against normal cell (WISH).

The miraculous golden tree of the century, neem or Azadirachta indica, has been used in ancient ayurvedic and traditional medicine since the inception of medicinal practices. The phytochemicals present in each part of this tree are known to possess the ability to cure a variety of diseases, from viral, bacterial, and fungal infections and associated pathogenesis to inflammatory diseases, different metabolic disorders, and cancers. Predominant phytochemicals from neem, azadirachtin, nimbin, nimbolide, quercetin, etc., are known to be potent anti-inflammatory, antiviral, and anti-cancer agents. These and many other bio-active compounds from neem restrict the viral spread and replication of β-coronaviruses, Human Immunodeficiency Virus, Herpes Simplex Virus, etc. Likewise, neem extracts and bio-active compounds from neem have been targeting cancer cells by restricting their proliferation, survival, and migration and inducing apoptosis, leading to the establishment of neem as a potent anti-cancer agent. Multiple studies have reported neem's efficiency in intervening with inflammatory pathways and oxidative stress pathways, which are known to be linked to viral infections and cancers. In this review, we discuss the role of methanolic neem bark extracts and their bio-active compounds in preventing β-coronavirus mouse hepatitis virus and SARS-CoV-2 replication and spread, and simultaneously the anti-cancer effects exerted by MNBE via activating pro-apoptotic markers, restricting the proliferation and migration of cervical cancer cells, inducing cell cycle arrest.

Metal complexes have been utilized in medicine for thousands of years in various ways, with positive benefits. They are well recognized as delivery and diagnostic agents with anti-infective, antimicrobial, antidiabetic, and neurological properties. Based on this, Co, Zn, and Cu complexes were synthesized using a Schiff base reaction and were fully characterized. The complexes were then assessed using breast cancer cell line (MDA-MB-453), and the data show that the Cu–ligand complex was the most potent anticancer agent, followed by the Zn complex, and then the Co complex. This result is supported by DFT theoretical calculations. In addition, the complexes were tested for their biological activities against both Gram-positive and Gram-negative bacteria, and the data reveal that Cu had a strong inhibitory effect on the growth of both types of bacteria. In summary, the copper complex proved to be a potent anticancer and antibacterial agent, and it can be considered for utilization in future therapies.

A simple pathway leading to 3-hydroxyquinoline-4(1H)-one-5-carboxamides was developed. Target compounds were identified as potential anticancer agents and fluorescent labels.

Mitochondria-targeted iridium complexes for anticancer studies have received increasing attention in recent years. Herein, three cyclometalated iridium(III) complexes Ir1-Ir3 [Ir(N^C)2(N^N)](PF6) (N^N = 2,2'-bipyridine (bpy)) or 2-(5-bromopyridin-2-yl)benzo[d]thiazole (bpybt); [N^C = 2-phenylpyridine (ppy) or 2-phenylquinoline (pq) or 2-(4-bromophenyl)benzo[d]thiazole (bpbt)] had been explored as potential mitochondria-targeted anticancer agents. All of the complexes mainly localized in the mitochondria and could be fixed on the mitochondria through a nucleophilic reaction with reactive mitochondrial proteins. Further studies revealed that these complexes showed high anticancer activity, induced mitochondrial depolarization, elevated intracellular reactive oxygen species (ROS) levels, restrained thioredoxin reductase (TrxR) activity, and inhibited the formation of tumor cell colonies and angiogenesis. Further mechanistic studies showed that complex Ir2 could markedly stimulate the activation of caspase-3, regulate the expression of Bax and KI67, and trigger apoptosis.

The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent

Structurally unique 6,7-seco-ent-kaurenes, which are widely distributed in the genus Isodon, have attracted considerable attention because of their antitumor activities. Previously, a convenient conversion of commercially available oridonin (1) to 6,7-seco-ent-kaurenes was developed. Herein, several novel spiro-lactone-type ent-kaurene derivatives bearing various substituents at the C-1 and C-14 positions were further designed and synthesized from the natural product oridonin. Moreover, a number of seven-membered C-ring-expanded 6,7-seco-ent-kaurenes were also identified for the first time. It was observed that most of the spiro-lactone-type ent-kaurenes tested markedly inhibited the proliferation of cancer cells, with an IC50 value as low as 0.55 μM. An investigation on its mechanism of action showed that the representative compound 7b affected the cell cycle and induced apoptosis at a low micromolar level in MCF-7 human breast cancer cells. Furthermore, compound 7b inhibited liver tumor growth in an in vivo mouse model and exhibited no observable toxic effects. Collectively, the results warrant further preclinical investigations of these spiro-lactone-type ent-kaurenes as potential novel anticancer agents.

Microbial amphiphiles: a class of promising new-generation anticancer agents

Seven new (2-chloroethyl)nitrosocarbamates have been synthesized as potential anticancer alkylating agents. These compounds were designed with carrier moieties that would either act as prodrugs or confer water solubility. All compounds were screened in an in vitro panel of five human tumor cell lines: CAKI-1 (renal), DLD-1 (colon), NCI-H23 (lung), SK-MEL-28 (melanoma), and SNB-7 (CNS). Several agents showed good activity with IC(50) values in the range of 1-10 microg/mL against at least two of the cell lines. One compound, carbamic acid, (2-chloroethyl)nitroso-4-acetoxybenzyl ester (3), was selected for further study in vivo against intraperitoneally implanted P388 murine leukemia. In addition to the aforementioned compound, both carbamic acid, (2-chloroethyl)nitroso-4-nitrobenzyl ester (9) and carbamic acid, (2-chloroethyl)nitroso-2,3,4, 6-tetra-O-acetyl-1-alpha,beta-D-glucopyranose ester (24) were evaluated against subcutaneously implanted M5076 murine sarcoma in mice. None of these compounds were active in vivo.

Specific strains of fluorescent pseudomonads produce a group of bioactive compounds such as phenazines, phloroglucinols, pyrrole-type compounds, polyketides, peptide antibiotics and neomycin. We have reported several novel forms of phenazines such as the dimeric form of phenazine carboxylic acid (PCA), 5-methyl phenazine-1-carboxylic acid betaine (MPCAB), phenazine-1-carboxamide (PCN) and different forms of phloroglucinol. Our recent findings also confirmed the broad-spectrum antimicrobial, anticancer and anti-inflammatory potential of pseudomonad metabolites. Considering the emergence of multiple drug resistance in the human pathogenic bacterial populations, new antimicrobial metabolites and their combinations are required to combat the diseases. Elucidation of the structural and functional features of pro-apoptotic and anti-apoptotic proteins has shed light upon their diverse roles in various cellular processes apart from apoptosis. Efforts are being made to translate the research evidence on molecular mechanisms of antimicrobial and anticancer potential to rationalise and ameliorate the development of effective drug molecules. In the light of the above, this chapter describes a detailed account on pseudomonad metabolites and their antimicrobial potential towards pathogens as well as their anticancer properties and signalling pathways.