Complexing the Marine Sesquiterpene Euplotin C by Means of Cyclodextrin-Based Nanosponges: A Preliminary Investigation.

Euplotin C is a sesquiterpene of marine origin endowed with significant anti-microbial and anti-tumor properties. Despite the promising functional profile, its progress as a novel drug candidate has failed so far, due to its scarce solubility and poor stability in aqueous media, such as biological fluids. Therefore, overcoming these limits is an intriguing challenge for the scientific community.

Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation.

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats.

Aldehyde Dehydrogenases and Prostate Cancer: Shedding Light on Isoform Distribution to Reveal Druggable Target.

Prostate cancer represents the most common malignancy diagnosed in men, and is the second-leading cause of cancer death in this population. In spite of dedicated efforts, the current therapies are rarely curative, requiring the development of novel approaches based on innovative molecular targets. In this work, we validated aldehyde dehydrogenase 1A1 and 1A3 isoform expressions in different prostatic tissue-derived cell lines (normal, benign and malignant) and patient-derived primary prostate tumor epithelial cells, demonstrating their potential for therapeutic intervention using a small library of aldehyde dehydrogenase inhibitors.

A 2,3-diphenylpyrido[1,2-] pyrimidin-4-one derivative inhibits specific angiogenic factors induced by TNF-α.

Low-grade chronic inflammation is a key process of angiogenesis in tumour progression. We investigated whether a synthetic analogue of apigenin, the 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a] pyrimidin-4-one (called DB103), interfered with the mechanisms involved in the angiogenic process induced by the inflammatory cytokine tumour necrosis factor (TNFα). In endothelial cells, DB103 but not apigenin reduced the TNFα-induced oxidative stress.

Dual Kit/Aur Inhibitors as Chemosensitizing Agents for the Treatment of Melanoma: Design, Synthesis, Docking Studies and Functional Investigation.

Melanoma is the most serious form of skin cancer but its medication is still far from being safe and thoroughly effective. The search of novel therapeutic approaches represents therefore a health emergency to push through eagerly. In this study, we describe a novel class of dual c-Kit/Aur inhibitors, characterized by a 1,2,4-triazole core and developed by a structure-based optimization of a previously developed hit, and report the evidence of their significance as drug candidates for the treatment of melanoma.

Aldose reductase inhibitors: 2013-present.

Introduction: Aldose reductase (ALR2) is both the key enzyme of the polyol pathway, whose activation under hyperglycemic conditions leads to the development of chronic diabetic complications, and the crucial promoter of inflammatory and cytotoxic conditions, even under a normoglycemic status. Accordingly, it represents an excellent drug target and a huge effort is being done to disclose novel compounds able to inhibit it.

Areas Covered: This literature survey summarizes patents and patent applications published over the last 5 years and filed for natural, semi-synthetic and synthetic ALR2 inhibitors.

Soyasaponins from Zolfino bean as aldose reductase differential inhibitors.

Seven triterpenoid saponins were identified in methanolic extracts of seeds of the Zolfino bean landrace (Phaseolus vulgaris L.) by HPLC fractionation, revealing their ability to inhibit highly purified human recombinant aldose reductase (hAKR1B1). Six of these compounds were associated by MS analysis with the following saponins already reported in different Phaseolus vulgaris varieties: soyasaponin Ba (V), soyasaponin Bb, soyasaponin Bd (sandosaponin A), soyasaponin αg, 3-O-[R-l-rhamnopyranosyl(1 → 2)-α-d-glucopyranosyl(1 → 2)-α-d-glucuronopyranosyl]olean-12-en-22-oxo-3α,-24-diol, and soyasaponin βg.

Antineoplastic Effect of Lenvatinib and Vandetanib in Primary Anaplastic Thyroid Cancer Cells Obtained From Biopsy or Fine Needle Aspiration.

Anaplastic thyroid carcinoma (ATC) is a malignant tumor of the thyroid gland, infrequent but with a very poor prognosis, as it rapidly causes death (mean survival of about 6 months). ATC treatment includes a multimodal protocol consisting of surgery, chemotherapy (doxorubicin and cisplatin), and hyperfractionated accelerated external beam radiotherapy (median patient survival of 10 months). For this reason, the identification of an effective systemic treatment for ATC would be a major advance in the management of this deadly thyroid cancer.

Acid Derivatives of Pyrazolo[1,5-a]pyrimidine as Aldose Reductase Differential Inhibitors.

Aldose reductase (AKR1B1), the key enzyme of the polyol pathway, plays a crucial role in the development of long-term complications affecting diabetic patients. Nevertheless, the expedience of inhibiting this enzyme to treat diabetic complications has failed, due to the emergence of side effects from compounds under development. Actually AKR1B1 is a Janus-faced enzyme which, besides ruling the polyol pathway, takes part in the antioxidant defense mechanism of the body.

Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors.

It is now known that "gain of function" mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET.

Novel quinazolinone-based 2,4-thiazolidinedione-3-acetic acid derivatives as potent aldose reductase inhibitors.

Aim: Targeting aldose reductase enzyme with 2,4-thiazolidinedione-3-acetic acid derivatives having a bulky hydrophobic 3-arylquinazolinone residue.

Materials & Methods: All the target compounds were structurally characterized by different spectroscopic methods and microanalysis, their aldose reductase inhibitory activities were evaluated, and binding modes were studied by molecular modeling.

Results: All the synthesized compounds proved to inhibit the target enzyme potently, exhibiting IC values in the nanomolar/low nanomolar range.

Quinazolinone-based rhodanine-3-acetic acids as potent aldose reductase inhibitors: Synthesis, functional evaluation and molecular modeling study.

A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat.

Cyclodextrin-based nanosponges for the targeted delivery of the anti-restenotic agent DB103: A novel opportunity for the local therapy of vessels wall subjected to percutaneous intervention.

Nano-sized colloidal carriers represent innovative drug delivery systems, as they allow a targeted and prolonged release of poorly water-soluble drugs, improving their bioavailability and modifying their pharmacokinetic parameters. In this work we describe cyclodextrin-based nanosponges, obtained through polimerization of β-cyclodextrin with diphenyl carbonate as the cross-linking agent, loaded with a novel multi-effective heterocyclic compound, DB103, able to regulate key cellular events involved in the remodelling of vessels wall. Fabrication and drug-loading procedures, as well as physical-chemical characterization and drug-release profile of the novel colloidal system are reported.

1,2-Benzisothiazole Derivatives Bearing 4-, 5-, or 6-Alkyl/arylcarboxamide Moieties Inhibit Carbonic Anhydrase Isoform IX (CAIX) and Cell Proliferation under Hypoxic Conditions.

Three novel series of 1,2-benzisothiazole derivatives have been developed as inhibitors of carbonic anhydrase isoform IX. Compounds 5c and 5j, tested in vitro on the human colon cell line HT-29, blocked the growth of cells cultured under chemically induced hypoxic conditions, displaying a specific activity against cancer cells characterized by CAIX up-regulation. Moreover, a synergistic activity of 5c with SN-38 (the active metabolite of irinotecan) and 5-fluorouracil on cell proliferation under hypoxic conditions was demonstrated.