Current Medicinal Chemistry (v.21, #20)

Bladder Cancer: Innovative Approaches Beyond the Diagnosis by R. Piergentili, S. Carradori, C. Gulia, C. De Monte, C. Cristini, P. Grande, E. Santini, V. Gentile, G.B. Di Pierro (2219-2236).
Bladder carcinoma (BC) is the most common urinary malignant tumor. In the light of the unsuccessful currenttherapies and their side effects, new pharmacological strategies are needed. In addition to the well known therapeutic possibilitiesdescribed in the first section, we focused our attention on very recent and innovative tools to approach this target(new drug candidates from epigenetic modulators to endothelin receptor inhibitors, improved technological formulations,active principles from plants, and dietary components). Then, in the last paragraph, we analyzed the etiology of recurrentBC, with particular attention to cellular microenvironment. In fact, the incidence of recurrence is up to 90%, and 25% oftumours show progression towards invasiveness.

The Combined Therapeutical Effect of Metal-based Drugs and Radiation Therapy: The Present Status of Research by C. Ceresa, A. Bravin, G. Cavaletti, M. Pellei, C. Santini (2237-2265).
Conventional chemotherapy and radiation treatment are two cornerstones of cancer treatment but efforts are requiredto improve their “therapeutic window”. The development of metal complexes, including platinum, has had anenormous impact on current cancer chemotherapy. However, these chemotherapeutic drugs can be employed only in themanagement of a limited number of cancers and, furthermore, their use causes significant side effects. Research over thepast 10 years has produced new complexes containing heavy atoms other than platinum, such as iron, cobalt, or gold,which have been used in phase I and phase II trials. Recent preclinical research has shown promising results also using titanium,ruthenium, copper and silver. The anticancer activity of metal-based compounds and nanoparticles (gold andgadolinium in particular) is presently under evaluation in several laboratories in combination with or without X-ray therapy.In fact, if present in sufficiently high concentrations in the tumors, metals can act as a radiotherapy adjuvant: theypossess an increased capability to absorb the X-ray radiation with respect to the water-based tissues. Low energy electronswill be then released close to the metal and, therefore, determine a local dose enhancement. This review will focus on theanticancer properties of new drugs and on the rationale for testing their usefulness in combined treatment.

Medicinal Electrochemistry: Integration of Electrochemistry, Medicinal Chemistry and Computational Chemistry by M.O. Almeida, V.G. Maltarollo, R.A. de Toledo, H. Shim, M.C. Santos, K.M. Honorio (2266-2275).
Over the last centuries, there were many important discoveries in medicine that were crucial for gaining a betterunderstanding of several physiological processes. Molecular modelling techniques are powerful tools that have been successfullyused to analyse and interface medicinal chemistry studies with electrochemical experimental results. This specialcombination can help to comprehend medicinal chemistry problems, such as predicting biological activity and understandingdrug action mechanisms. Electrochemistry has provided better comprehension of biological reactions and, as a resultof many technological improvements, the combination of electrochemical techniques and biosensors has become an appealingchoice for pharmaceutical and biomedical analyses. Therefore, this review will briefly outline the present scopeand future advances related to the integration of electrochemical and medicinal chemistry approaches based on variousapplications from recent studies.

Misfolding of Apoprotein B-100, LDL Aggregation and 17-β -estradiol in Atherogenesis by R. Brunelli, M. De Spirito, G. Mei, M. Papi, G. Perrone, C. Stefanutti, T. Parasassi (2276-2283).
The long quest for a missing mechanistic rationale accounting for the correlation between plasma cholesterol levelsand cardiovascular disease (CVD) has been focused on various possible modifications of low density lipoprotein (LDL), turningthis physiological cholesterol carrier into a damaging agent able to trigger atherogenesis and later the onset of the disease.In addition to the debated oxidized LDL (oxLDL), a modified LDL with a misfolded apoprotein B-100, called electronegativeLDL(-) for its negative charge due to an increased amount of free fatty acids, is commonly present in plasma. LDL(-) isgenerated by the action of secretory calcium dependent phospholipase A2. LDL(-) primes LDL aggregation and amyloidformation according to mechanisms very similar to those observed in other misfolding diseases. The LDL particle aggregatesrecall the structure and size of the subendothelial lipid droplets described in early atherogenesis and elicit a powerful inflammatoryresponse. The use of 17-β-estradiol (E2) confirmed that the suggested atherogenicity of LDL (-) is mostly dependenton the misfolded character of its apoprotein. E2 binding to the apoprotein of native LDL, through a specific and saturable receptor,inhibits misfolding phenomenon despite an unaffected production of LDL (-) by phospholipase A2, ultimately preventingLDL aggregation. The apoprotein misfolding in LDL(-) emerges as a possible significant trigger mechanism ofatherogenesis. Potential implications for the development of novel therapeutic approaches might be hypothesized in perspective.The existing evidence is discussed and reported in this review.

Benzimidazole Derivatives as Kinase Inhibitors by Laura Garuti, Marinella Roberti, Giovanni Bottegoni (2284-2298).
Benzimidazole is a common kinase inhibitor scaffold and benzimidazole-based compounds interact with enzymesby multiple binding modes. In some cases, the benzimidazole acts as part of the hinge-binding motif, in others ithas a scaffolding role without evidence for direct hinge binding. Several of these compounds are ATP-competitive inhibitorsand show high selectivity by exploiting unique structural properties that distinguish one kinase from the majority ofother kinases. However, the high specificity for a single target is not always sufficient. Thus another approach, calledmulti-target therapy, has been developed over the last few years. The simultaneous inhibition of various kinases may beuseful because the disease is attacked at several relevant targets. Moreover, if a kinase becomes drug-resistant, a multitargeteddrug can act on the other kinases. Some benzimidazole derivatives are multi-target inhibitors. In this article benzimidazoleinhibitors are reported with their mechanisms of action, structure-activity relationship (SAR) and biologicalproperties.

Antimicrobial Peptides: Promising Compounds Against Pathogenic Microorganisms by J. Cruz, C. Ortiz, F. Guzmán, R. Fernández-Lafuente, R. Torres (2299-2321).
In the last decades, the indiscriminate use of conventional antibiotics has generated high rates of microbial resistance.This situation has increased the need for obtaining new antimicrobial compounds against infectious diseases.Among these, antimicrobial peptides (AMPs) constitute a promising alternative as therapeutic agents against variouspathogenic microbes. These therapeutic agents can be isolated from different organisms, being widespread in nature andsynthesized by microorganisms, plants and animals (both invertebrates and vertebrates). Additionally, AMPs are usuallyproduced by a non-specific innate immune response. These peptides are involved in the inhibition of cell growth and inthe killing of several microorganisms, such as bacteria, fungi, enveloped viruses, protozoans and other parasites. Theyhave many interesting properties as potential antibiotics, such as relatively small sizes (below 25-30 kDa), amphipathicstructures, cationic nature, and offer low probability for the generation of microbial resistance. In recent years, manynovel AMPs, with very promising therapeutic properties, have been discovered. These peptides have been the base for theproduction of chemical analogs, which have been designed, chemically synthesized and tested in vitro for their antimicrobialactivity. This review is focused on antibacterial (against Gram (-) and Gram (+) bacteria) and antifungal peptides, discussingaction mode of AMPs, and recent advances in the study of the molecular basis of their anti-microbial activity. Finally,we emphasize on their current pharmacological development, future directions and applications of AMPs as promisingantibiotics of therapeutic use for microbial infections.

In Vitro, In Vivo and In Silico Analysis of the Anticancer and Estrogen-like Activity of Guava Leaf Extracts by L.Y. Rizzo, G.B. Longato, A.LT.G. Ruiz, S.V. Tinti, A. Possenti, D.B. Vendramini-Costa, A. Sartoratto, G.M. Figueira, F.L.N. Silva, M.N. Eberlin, T.A.C.B. Souza, M.T. Murakami, E. Rizzo, M.A. Foglio, F. Kiessling, T. Lammers, J.E. Carvalho (2322-2330).
Anticancer drug research based on natural compounds enabled the discovery of many drugs currently used incancer therapy. Here, we report the in vitro, in vivo and in silico anticancer and estrogen-like activity of Psidium guajavaL. (guava) extracts and enriched mixture containing the meroterpenes guajadial, psidial A and psiguadial A and B. Allsamples were evaluated in vitro for anticancer activity against nine human cancer lines: K562 (leukemia), MCF7 (breast),NCI/ADR-RES (resistant ovarian cancer), NCI-H460 (lung), UACC-62 (melanoma), PC-3 (prostate), HT-29 (colon),OVCAR-3 (ovarian) and 786-0 (kidney). Psidium guajava's active compounds displayed similar physicochemical propertiesto estradiol and tamoxifen, as in silico molecular docking studies demonstrated that they fit into the estrogen receptors(ERs). The meroterpene-enriched fraction was also evaluated in vivo in a Solid Ehrlich murine breast adenocarcinomamodel, and showed to be highly effective in inhibiting tumor growth, also demonstrating uterus increase in comparison tonegative controls. The ability of guajadial, psidial A and psiguadials A and B to reduce tumor growth and stimulate uterusproliferation, as well as their in silico docking similarity to tamoxifen, suggest that these compounds may act as SelectiveEstrogen Receptors Modulators (SERMs), therefore holding significant potential for anticancer therapy.