Medicinal Chemistry - Volume 12, Issue 2, 2016

In the beginning, atherosclerosis was considered to be the result of passive lipid accumulation in the vascular walls. After tremendous technological advancements in research, we are now able to almost admire the complexity of the atherosclerotic process. Atherosclerosis is a chronicinflammatory condition that begins with the formation of calcified plaque, influenced by a number of different factors inside the vascular wall in large and mid-sized arteries. Calcium mineralization of the lumen in the atherosclerotic artery promotes and solidifies plaque formation causing narrowing of the vessel. Soft tissue calcification associated with tissue denegation or necrosis is a passive precipitation event. The process of atherogenesis is mainly driven by CD4+ T cells, CD40L, macrophages, foam cells with elevated transcription of many matrix metalloproteinases, osteoblasts, cytokines, selectins, myeloperoxidases, vascular adhesion molecules (VCAM), and smooth muscle cells. Our knowledge in the genesis of atherosclerosis has changed dramatically in the last few years. New imaging techniques such as intravascular ultrasound or IVUS have made possible to investigate atherosclerosis in early stages. Arterial calcification emerges from two different types, the medial-elastin dependent and the intimal, both of which are directly related to atherosclerosis due to osteoblast differentiation of vascular smooth muscle cells. The deposition of minerals in the form of calcium (Ca2+) initially emerges from the inorganing mineral octacalcium phosphate [Ca8H2(PO4)6.5H2O] to the form of Hydroxylapatite [Ca10(PO4)6(OH)2]. This review is devoted to broaden the understanding regarding atherosclerosis and the central role of calcium in the development of the condition.

Coronary Heart Disease (CHD) is the major mortality cause in the Western Hemisphere. Reinstituting blood flow in the acutely occluded coronary vessel became the standard intervention to prevent Myocardial Infarct (MI) progression. Ever since their conception, thrombolysis, Percutaneous Coronary Intervention (PCI) and Coronary Artery Bypass Grafting (CABG) have been at the forefront of CHD treatment, limiting MI size. However, it quickly became apparent that after a period of ischemia, reperfusion itself sets off a cascade of events leading to cell injury. It seems that cellular changes in the ischemic period, prime the cell for a loss of homeostasis once blood flow returns. Loss of calcium (Ca2+) regulation has been found to be a main culprit in both ischemia and reperfusion. Indeed, sarcoplasmic Ca2+ overload during reperfusion is related to hypercontracture, proteolysis and mitochondrial failure - the so-called Reperfusion Injury (RI). Ca2+ channels of the sarcolemma (SL) (L-Type Ca2+ Channels, Sodium / Calcium Exchanger) initiate Ca2+ flux and those of the Sarcoplasmic Reticulum (SR) (Ca2+ ATPase, Ca2+ release channel) sustain the rise in intracellular Ca2+ concentration. Ensuing interplay between Ca2+, SR, mitochondria, myofilaments and proteolytic cascades i.e. calpain activation, results in cell injury. Novel insight about this interplay and details about the extent by which each of these players contributes to the RI, may allow scientists to devise and design proper interventions that ultimately reduce RI in clinical practice. The present article reviews the literature about key subcellular players participating in the sustained rise of cardiac myocyte cytosolic Ca2+ during ischemia and reperfusion.

Platelets are involved in haemostasis and vessel integrity under physiologic conditions, and in thrombosis under disease states. Platelet activation upon stimulation with various agonists in vitro and in vivo, is strongly dependent on an increase of intracellular Ca2+ concentration. The latter results from Ca2+ release by the dense tubular system (DTS), and Ca2+ entry from the extracellular space. Recent advances in identification of the molecular mechanisms involved in these processes are described in this review, along with potential targets for pharmacologic interventions in disease states.

Inherited cardiomyopathies are a known cause of heart failure, although the pathways and mechanisms leading from mutation to the heart failure phenotype have not been elucidated. There is strong evidence that this transition is mediated, at least in part, by abnormal intracellular Ca2+ handling, a key ion in ventricular excitation, contraction and relaxation. Studies in human myocytes, animal models and in vitro reconstituted contractile protein complexes have shown consistent correlations between Ca2+ sensitivity and cardiomyopathy phenotype, irrespective of the causal mutation. In this review we present the available data about the connection between mutations linked to familial hypertrophic (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathy, right ventricular arrhythmogenic cardiomyopathy/dysplasia (ARVC/D) as well as left ventricular non-compaction and the increase or decrease in Ca2+ sensitivity, together with the results of attempts to reverse the manifestation of heart failure by manipulating Ca2+ homeostasis.

Although HF has multiple causes amongst which coronary artery disease, hypertension and non-ischemic dilated cardiomyopathy are the most common, it results in the same final common pathway of neurohormonal activation and multiorgan dysfunction in the context of a salt-avid state. Contemporary pharmacologic HF therapy targets neurohormonal activation at multiple levels with β- blockers, angiotensin converting enzyme inhibitors, and aldosterone inhibitors, aiming in reversing both its systemic consequences, and the adverse heart remodeling, however is frequently hampered by side effects of the drugs, limiting its benefit. During the last 40 years studies of the gross and molecular aspects of the pathophysiology of HF convincingly converge to the conclusion that deranged calcium (Ca2+) handling in the cardiomyocytes plays a cardinal role in HF initiation and progression. The delicate and precise regulation of Ca2+ cycling i.e. movement into and out of the cell, as well as into and out of the sarcoplasmic reticulum (SR), is finely tuned by numerous macromolecular proteins and regulatory processes like phosphorylation and dephosphorylation, and is severely deranged in HF. The common denominator in this scenario is Ca2+ depletion of the SR, however loading of cardiomyocytes with Ca2+ as a result of classic inotropic therapy has proved to be detrimental in the long term. Therefore, the mediator and/or regulatory components of the Ca2+ cycling apparatus have been the focus of extensive research involving targeted pharmacologic and gene interventions aiming to a restoration of Ca2+ cycling processes, thus improving inotropy and lucitropy in a more “physiologic” way in the failing myocardium.

Pulmonary arterial hypertension (PAH) is a serious life threatening disease that leads to right heart failure and death. Elevated pulmonary vascular resistance (PVR) is the main pathophysiological component that leads to elevated pulmonary arterial pressures and increased right ventricular afterload. Increased PVR is related to different mechanisms that include vasoconstriction, proliferative and obstructive remodeling of the pulmonary vessel wall and in situ thrombosis. Numerous molecular, genetic and humoral abnormalities have been proposed to play an important role in pulmonary vasoconstriction and remodeling. Of those, calcium (Ca+2) is a well recognized parameter involved in the pathogenetic mechanisms of PAH, because of its twofold role in both vasoconstriction and pulmonary artery smooth muscle cell (PASMC) proliferation. The aim of this review is to focus on Ca+2 handling and dysregulation in PASMC of PAH patients.

Intracellular calcium homeostasis plays a fundamental role in the electric and mechanical function of the heart by modulating action potential pattern and duration, by linking cell membrane depolarization to myocardial contraction and by regulating cardiac automaticity. Abnormalities of intracellular calcium regulation disrupt the electrophysiological properties of the heart and create an arrhythmogenic milieu, which promotes atrial and ventricular arrhythmogenesis and impairs cardiac automaticity and atrioventricular conduction. In this brief review, we summarize the basic genetic, molecular and electrophysiological mechanisms linking inherited or acquired intracellular Ca2+ dysregulation to arrhythmogenesis.

Cardiovascular disease is the leading cause of death worldwide and there is extensive research on the pathophysiology of all its clinical entities. Despite the big array of possible therapeutic modalities for cardiovascular disease, there is still a big necessity to develop novel treatments that will augment our strategies for tackling the burden of cardiovascular disease and decrease morbidity and mortality. A major player in both the physiology and pathophysiology of the cardiovascular system is calcium. Extracellular calcium is required in order to initiate cardiac muscle contraction and promote the calcium-induced calcium release mechanism from the sarcoplasmic reticulum. A lot of molecules and structures that in a direct or indirect way interact with calcium are being studied and there is a constant flow of new information that is emerging. In this review we focus on some of these calcium metabolism modulators representatives such as SERCA2a, RyR2, S100A1, phosholamban and calcineurin. We emphasize on their mechanism of action, their role in cardiovascular disease and potential therapeutic implications. We also focus on the effect the bisphosphonates might have in regression of the calcium deposition in the human arteries as well as the usage of novel biomarkers such as mircoRNAs in calcium metabolism modulation in heart disease.

Harmine 1 was extracted from the seeds of Peganum harmala. From this natural molecule, a new series of isoxazole derivatives with complete regiospecificity were prepared using 1,3-dipolar cycloaddition reactions with various arylnitrile oxides. Harmine and its derivatives were characterized by 1H NMR, 13C NMR and HRMS. The evaluation of their anti-acetylcholinesterase (AChE), anti-5-lipoxygenase (5-LOX), anti-xanthine oxidase (XOD) and anticancer activities were studied in vitro against AChE, 5-LOX and XOD enzymes, respectively, and in HTC-116, MCF7 and OVCAR-3 cancer cell lines. The prepared derivatives were shown to be inactive against the XOD enzyme (0-38.3±1.9% at 100 μM). Compound 2 exhibited the best anti-AChE activity (IC50=1.9±1.5 μM). Derivatives 3a, 3b and 3d had moderate cytotoxic activities (IC50=5.0±0.3 μM (3a) and IC50=6.3±0.4 μM (3b) against HCT 116 cells, IC50=5.0±1.0 μM (3d) against MCF7 cells).

Background: Previously, modification of isoniazide- and pyrazinamide-derived pharmacophores via the Ugi multicomponent reaction proved to be an effective strategy to obtain efficacious and non-cytotoxic antimycobacterial leads. Objective: To apply the hydrazino-Ugi reaction developed in our group toward modifying these pharmacophores with similar appendages as reported previously; to create hydrolytically more stable compounds which are based on acyl hydrazine, rather than diamide backbone. Method: Six hydrazino-Ugi products were synthesized and modified at the reactive nitrogen atom via reductive alkylation. Additionally, by conducting the hydrazino-Ugi reaction in methanol, three methyl ester by-products were obtained and tested alongside the main library. Compounds were screened against M. tuberculosis H37Rv strain and checked for cytotoxicity vs. HEK293 cells. Hydrolytic stability of a model Ugi and one of the newly synthesized hydrazino-Ugi products was compared in rat plasma stability experiments. Results: 6 out of 20 compounds prepared and tested, displayed potent inhibition of M. tuberculosis growth and virtually no cytotoxicity in the testing concentration range. The stability of a sample hydrazino-Ugi product in rat plasma was over 3 times higher compared to that of one of the Ugi products reported earlier. Conclusion: Hydrazino-Ugi reaction represents an effective way to modify classical antitubercular chemotypes and generate compounds endowed with specific antimycobacterial activity. These are new, hydrolytically stable leads for the future antitubercular therapy development.