Small Molecules of Marine Origin as Potential Anti-Glioma Agents

Abstract

Marine organisms are able to produce a plethora of small molecules with novel chemical structures and potent biological properties, being a fertile source for discovery of pharmacologically active compounds, already with several marine-derived agents approved as drugs. Glioma is classified by the WHO as the most common and aggressive form of tumor on CNS. Currently, Temozolomide is the only chemotherapeutic option approved by the FDA even though having some limitations. This review presents, for the first time, a comprehensive overview of marine compounds described as anti-glioma agents in the last decade. Nearly fifty compounds were compiled in this document and organized accordingly to their marine sources. Highlights on the mechanism of action and ADME properties were included. Some of these marine compounds could be promising leads for the discovery of new therapeutic alternatives for glioma treatment.

EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy

“…On the other hand, its less in vitro EGFR inhibitory activity compared to that of erlotinib could be explained by the lack of key interaction with Met769 (Figure 8). As compared to costly and time-consuming absorption, distribution, metabolism cretion (ADME) experimental procedures [40], computational models are advantag approaches to provide access to a set of rapid, yet robust predictive models for phy chemical, and pharmacokinetic properties [10]. In this direction, we performed in predictions of some pharmacokinetic parameters of the compounds by the QikPro predictive ADME module within the Maestro suite produced by Schrödinger.…”

“…Taking into account the importance o drogen bonding with pivotal residues in the ATP binding site of EGFR, the numb donor (nHBD) and acceptor (nHBA) sites for hydrogen bonds were calculated. Appro ate nHBD (0 to 4) and nHBA (3.7 to 7.2) values of all compounds within the limits (0 and 2 to 20, respectively) also supported the outcomes of the molecular docking st Solvent accessible surface area (SASA) is defined as the accessibility of the residue to solvent; either it is between lipid or water accessibility and it is also essential to BBB As compared to costly and time-consuming absorption, distribution, metabolism, excretion (ADME) experimental procedures [40], computational models are advantageous approaches to provide access to a set of rapid, yet robust predictive models for physicochemical, and pharmacokinetic properties [10]. In this direction, we performed in silico predictions of some pharmacokinetic parameters of the compounds by the QikProp, a predictive ADME module within the Maestro suite produced by Schrödinger.…”

“…The BBB, which is the major impediment in drug delivery to the tumor [46], limits the efficacy of anti-glioma agents [10]. In order to overcome this problem, the discovery of antiglioma agents endowed with a favorable pharmacokinetic profile and bioavailability along with the ability to cross the BBB is of great importance and, therefore ADME properties are critical features for anti-glioma agents to consider [3].…”

“…Among these four grades [6], glioblastoma multiforme (GBM; grade IV) is the most common, aggressive, and malignant form of glioma [7,8]. The main features of GBM are rapid proliferation with poor differentiation, diffuse infiltration into normal brain tissues, angiogenesis, tendency to necrosis, resistance to apoptosis, widespread genomic aberrations [8,9], and these features make GBM challenging to treat [8][9][10][11]. Current treatment protocol involves surgical resection followed by concurrent radiotherapy and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months [1,8].…”

“…The inherent chemoresistance of the brain endothelium and glioma cells, expressing the drug efflux protein p-glycoprotein also impairs the therapeutic efficacy [2,3]. Moreover, clinical applications are limited by adverse effects, such as bone marrow suppression, genotoxic, and teratogenic effects [10].…”