Mini Reviews in Medicinal Chemistry - Volume 17, Issue 9, 2017

Background: The aminocoumarin antibiotic, novobiocin, is a natural product that inhibits DNA gyrase, a bacterial enzyme involved in cell division. Method: More recently, novobiocin was found to act also on eukaryotic cells by blocking the 90 kDa heat shock protein (Hsp90). Hsp90 is a molecular chaperone, critical for folding, stabilization and activation of many proteins, in particular oncoproteins responsible for cancer progression. As opposed to the geldanamycin and radicicol, the known inhibitors of Hsp90 that bind to the N-terminal region, the binding domain of novobiocin is localized in the C-terminal part of this protein. While the N-terminal inhibition also leads to the induction of some pro-survival signals, C-terminal inhibitors in which prosurvival responses are avoided and client degradation is maintained can be developed as a new class of potential anticancer chemotherapeutics. Numerous novobiocin analogs have been designed in the search for more potent compounds and some of them exhibit significantly enhanced anti-proliferative activity versus the natural product, as evaluated by cellular efficacies against several cancer cell lines. Conclusion: This review describes structure-activity-relationships of novobiocin analogs and some biological data reported so far on the anticancer activity of these modified compounds.

Background: Mycophenolic acid (MPA) possesses antibacterial, antifungal, antiviral, immunosuppressive and anticancer properties. It is a non-competitive and reversible inhibitor of dehydrogenase inosine-5'-monophosphate (IMPDH). This compound belongs to the immunosuppressive drugs used for the prevention of both acute and chronic transplant rejection. Until now, two derivatives of MPA have been used clinically: mycophenolate mofetil (MMF, CellCept) and mycophenolate sodium (MPS, Myfortic). They cause, similar to MPA, although at lower degree, the side effects such as vomiting, abdominal pain, diarrhea, nausea, gastrointestinal, urogenital tract, blood or nervous system disorders. These drawbacks and glucuronidation of MPA in vivo limit the use of these compounds as pharmaceuticals. Therefore, research is still going on for more effective analogs that are less toxic to the organism and could improve the quality of life of patients. Conclusion: In this review article, the authors present the synthesis of novel derivatives of mycophenolic acid, together with their initial biological investigations.

Background: In 1995, the Biopharmaceutics Classification System (BCS) was proposed by Amidon and colleagues as a tool that considers two important parameters regarding drugs: solubility and permeability. Since then, several methods for solubility and permeability studies have been developed for drug delivery and absorption prediction. In recent years, permeability has gained a great highlight and the interaction between a molecule and a biological membrane is not enough to predict the in vivo behavior of a compound. Method: Thus, different methods for permeability assessment are currently used for mechanistic studies including involvement of carriers and several transport pathways. Furthermore, the investigation regarding metabolism has been a focus in recent researches. Based on this idea, Wu and Benet proposed a new tool called Biopharmaceutics Drug Disposition Classification System (BDDCS), where drugs are classified into four classes considering their solubility and metabolism. Results: Among several methods for permeability studies, the in situ intestinal perfusion is considered the closest to in vivo conditions due advantages as intact blood supply and innervation. Conclusion: This review presents the in situ intestinal perfusion model and its application for permeability/transport studies of drugs and intestinal metabolism. Also, this paper discusses about how the in situ perfusion studies can be used for classification of drugs and the future perspectives for in vivo absorption prediction.

Background: Radiolabeled peptides, designed to bind with high affinity receptors selectively expressed on cell membranes of different human tissues, represent valuable tools for in vivo imaging of several human diseases. Solid-phase peptide synthesis as well as availability of bifunctional chelating agents and prosthetic groups allows the production and radiolabeling of several peptidebased molecules which are useful to target specific receptors on different cancer types. Among them, octreotide and other analogues of somatostatin, vasoactive intestinal peptide, CCK analogues, bombesin, α-MSH analogues, neurotensin, exendin, RGD, substance P, conjugated to appropriate chelators, such as DTPA, NOTA, DOTA or TETA, and radiolabeled with specific radionuclides, have already been translated into the clinical practice with remarkable sensitivity and diagnostic accurateness. Conclusion: This review recapitulates the current applications in clinical practice of radiolabeled peptides with particular attention to those employed for diagnosis and therapy in oncologic as well as nononcologic human diseases.

Background: The recent advances for the synthesis and application of different metallocenes for Medicinal Chemistry is reviewed. Objective: This manuscript presents the different metallocene scaffolds, with special emphasis on ferrocene derivatives, and their potential pharmaceutical application. Over the last years, the synthesis of new metallocene compounds and their biological and medicinal effects against some types of diseases (e.g. anti-tumoral, antibiotics, anti-viral) have been reported. From the medicinal point of view, the attractive properties of metallocene derivatives, such as their high stability, low toxicity and appealing redox behaviors are particularly relevant. Results: This area has attracted many researchers as well as the pharmaceutical industry due to the promising results of some metallocenes, in particular ferrocene compounds, in breast cancer and malaria.

Background: Skin pigmentation is a broadly appearing phenomenon in nature which plays an important task of determining the appearance and biology of all vertebrates including human beings. Skin color is a crucial attribute, determined by the synthesis of melanin pigment within melanocytes by the process of melanogenesis and is regulated by many extrinsic as well as intrinsic factors. Tyrosinase catalyzes the key step of melanogenesis, dysfunction of tyrosinase leads to reduce melanin production which results in severe clinical and aesthetical problems of hypopigmentation. Therefore, the regulation of melanin production is an important strategy in the treatment of abnormal skin pigmentation for cosmetic and medicinal purpose. Method: The present review covers the various aspects of mammalian melanocyte biology which will help in the identification of key regulators of melanogenesis from pharmaceutical and pharmacological point of view. Further sections of the review focus on the dysfunctions of melanogenic pathways, which result in severe clinical and aesthetical problems of hypopigmentation. Conclusion: We have also attempted to highlight the ability of available scientifically validated plant extracts to naturally enhance melanin synthesis in order to cure hypopigmentation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide and represent a mainstay in the therapy of acute and chronic pain and inflammation. The traditional NSAIDs like ibuprofen (I) contain free carboxylic acid group which can produce gastrointestinal (GI) damage for long-term use. Objective: In order to obtain the novel NSAIDs with less side effects; carboxylic acid moiety has been modified into various amide groups which is the most active area of research in this family. Method: In this research, synthesis of various pharmacological heterocyclic amides of ibuprofen is described. All the new compounds were tested for their analgesic and anti-inflammatory activities in mice and compared with standard (Ibuprofen) and control (saline) groups. Results & Conclusion: The results revealed that all the synthesized compounds (III-VI) exhibited more analgesic and anti-inflammatory activities in tail immersion (as a model of acute thermal pain), formalin (as a model of acute chemical and chronic pain) and paw edema (as a model of acute inflammation) tests when compared with standard and control animals. These pharmacological activities were significant for VI compared to other new compounds (III-V) which may be concern to more effective role of morpholin for the reduction of pain and inflammation compared to other used heterocyclic amines.

Method: A series of novel thiazole derivatives were synthesized in a good yield via reaction of 2-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)hydrazine carbothioamide with hydrazonoyl halides. The reaction was performed in the presence of DABCO as an organocatalyst in short reaction times, easy workup, good to excellent yields. The structure of the newly synthesized products was elucidated via elemental analysis, spectral data and alternative routes whenever possible. Ten compounds were evaluated for their anti-cancer activity against the colon carcinoma cell line (HCT-116). Results & Conclusion: The results revealed that most of the tested compounds showed high or moderate anti-cancer activity. The molecular docking of five novel thiazolyl-thiazole derivatives was performed by the Molecular Operating Environment (MOE) program.