Mini Reviews in Medicinal Chemistry - Volume 12, Issue 7, 2012

After binding to the neurokinin-1 (NK-1) receptor, substance P (SP) induces tumor cell proliferation, angiogenesis, and the migration of tumor cells for invasion and metastasis. After binding to NK-1 receptors, NK-1 receptor antagonists inhibit tumor cell proliferation, angiogenesis and the migration of tumor cells. These antagonists are broad-spectrum antitumor drugs. In addition, in the host they display beneficial effects: anxiolytic, antiemetic, neuroprotector, nephroprotector, hepatoprotector, antiinflammatory and analgesic. In combination therapy with classic cytostatics, NK-1 receptor antagonists have synergic effects and minimize the side-effects of these classic drugs. Thus, NK-1 receptor antagonists could offer a new and promising generation of anticancer drugs.

Nitric oxide (NO), which is produced by oxidation of L-arginine to L-citrulline in a process catalyzed by different isoforms of nitric oxide synthase (NOS), exhibits diverse roles in several physiological processes, including neurotransmission, blood pressure regulation and immunological defense mechanisms. On the other hand, an overproduction of NO is related with several disorders as Alzheimer’s disease, Huntington´s disease and the amyotrophic lateral sclerosis. Taking melatonin as a model, our research group has designed and synthesized several families of compounds that act as NOS inhibitors, and their effects on the excitability of N-methyl-D-aspartate (NMDA)-dependent neurons in rat striatum, and on the activity on both nNOS and iNOS were evaluated. Structural comparison between the three most representative families of compounds (kynurenines, kynurenamines and 4,5-dihydro-1H-pyrazole derivatives) allows the establishment of structure-activity relationships for the inhibition of nNOS, and a pharmacophore model that fulfills all of the observed SARs were developed. This model could serve as a template for the design of other potential nNOS inhibitors. The last family of compounds, pyrrole derivatives, shows moderate in vitro NOS inhibition, but some of these compounds show good iNOS/nNOS selectivity. Two of these compounds, 5-(2-aminophenyl)-1H-pyrrole-2-carboxylic acid methylamide and cyclopentylamide, have been tested as regulators of the in vivo nNOS and iNOS activity. Both compounds prevented the increment of the inducible NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS) observed in a MPTP model of Parkinson´s disease.

Marine invertebrates are a rich source of novel, bioactive secondary metabolites and have attracted a great deal of attention from scientists in the fields of chemistry, pharmacology, ecology, and molecular biology. This profilic natural source has produced several antitumor secondary metabolites and amongst these, indole alkaloids are of wide occurrence. Meridianins A-G (1-7) are indole alkaloids isolated from tunicate Aplidium meridianum and are known to inhibit variety of protein kinases associated with cancer and neurodegenerative diseases. These compounds also exhibited promising antiproliferative activity in several cancer cell lines. Amongst natural meridianins, meridianin E (5) showed potent and selective inhibition of CDK-1 and CDK-5. Several synthetic meridianin analogs exhibited potent and selective inhibition of glycogen synthase-3 (GSK-3) and dual-specificity tyrosine-phosphorylation regulated kinase 1A (Dyrk-1A) which are known to be implicated in progression of Alzheimer’s disease. The present review provides the critical account of isolation, medicinal chemistry and pharmacology of meridianins. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer and anti-Alzheimer’s agents.

Chromone alkaloids and flavoalkaloids are an important group of natural products possessing promising medicinal properties. A chromone alkaloid rohitukine is a major bioactive chemical constituent of plant Dysoxylum binectariferum (Meliaceae) Hook. which is phylogenetically related to the Ayurvedic plant, D. malabaricum Bedd. used for treatment of rheumatoid arthritis. This chromone alkaloid led to discovery of two synthetic flavoalkaloids: flavopiridol (Sanofi) and P-276-00 (Piramal) which have reached to advanced stages of clinical development for cancer treatment. Flavopiridol (Alvocidib; L868275; HMR-1275; NSC 649890 of Sanofi-Aventis + NCI) is approved as an orphan drug for treatment of chronic lymphocytic leukemia and is currently undergoing phase II studies as monotherapy and also as in combination regimes with traditional chemotherapy agents. P-276-00 (12) is currently in phase II clinical studies for advanced refractory neoplasms and multiple myeloma. Extensive amount of medicinal chemistry efforts have been reported on these flavoalkaloids. Flavopiridol demonstrated potent and specific in vitro inhibition of variety of cyclindependent kinases with clear block in cell cycle progression at the G1/S and G2/M phases. Preclinical studies demonstrated the capacity of flavopiridol to induce programmed cell death, promote differentiation, inhibit angiogenic processes and modulate transcriptional events. The co-crystallised structure of deschloro-flavopiridol with CDK-2 is available and key interactions in the ATP binding site have been reported. Flavopiridol has also been studied for the treatment of arthritis and atherosclerotic plaque formation. The present review comprises discovery, medicinal chemistry, pharmacology and preclinical/clinical development of flavoalkaloids as CDK inhibitors.

Marine natural products offer an abundant source of pharmacologically active agents with great diversity and complexity, and the potential to produce valuable therapeutic entities. Indole alkaloids is one of the important class of marine-derived secondary metabolites, with wide occurrence amongst variety of marine sources such as sponges, tunicates, algae, worms and microorganisms and have been extensively studied for their biological activities. Among this chemical family, a sponge-derived bis-indole alkaloid fascaplysin (1) exhibited broad range of bioactivities including antibacterial, antifungal, antiviral, anti-HIV-1-RTase, p56 tyrosine kinase inhibition, antimalarial, anti-angiogenic, antiproliferative activity against numerous cancer cell lines, specific inhibition of cyclin-dependent kinase-4 (IC50 350 nM) and action as a DNA intercalator. In the present review, the chemical diversity of natural as well as synthetic analogues of fascaplysin has been reviewed with a detailed account on synthetic reports and pharmacological studies. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer agents.

The pseudotrisaccharide allosamidin 1 is a potent family-18 chitinase inhibitor, and it demonstrates biological activities against insects and fungi. Recent development for the synthesis and activities of compound 1 and its analogues was reviewed. Huang et al. described the solid-phase synthesis of allosamidin 1 and its analogues, which were obtained by iterative glycosylation reactions, catalytic hydrogenation, acetylation, and deacetylation, respectively. It indicated that di-N-acetyl-β-chitobiosyl allosamizoline was strongly against insect chitinase from Bombyx mori. Withers and his coworkers have synthesized chitobiose and chitotriose thiazolines, which exhibit chitinase inhibition activity.

Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. There has been a considerable interest in the development of many antiepileptic and anticonvulsant agents for controlling epilepsy with fewer side effects and improvement of quality of life. Since the terms antiepileptics /anticonvulsants are used interchangeably, this article reviews their classification according to the chemical structure into: hydantoins, oxazolidinediones, succinimides, barbiturates, amides, benzodiazepines, valproic acid and its derivatives, GABAanalogues, cycloalkanes, semicarbazones, γ butyrolactones (GBLs), imidaquinazolines and pyrrolidine derivatives as well as miscellaneous compounds. In addition, the review discusses the different mechanisms of action of antiepileptic and anticonvulsant agents.