Mini Reviews in Medicinal Chemistry - Volume 13, Issue 6, 2013

Recently the aqueous medium has attracted the interest of organic chemists, and many. Moreover, in the past 20 years, the drug-discovery process has undergone extraordinary changes, and high-throughput biological screening of potential drug candidates has led to an ever-increasing demand for novel drug-like compounds. Noteworthy advantages were observed during the course of study on aqua mediated synthesis of compounds of medicinal importance. The established advantages of water as a solvent for reactions are, water is the most abundant and available resource on the planet and many biochemical processes occur in aqueous medium. This review will focus on describing new developments in the application of water in medicinal chemistry for the synthesis of bio-active compounds possessing various biological properties.

Cross-coupling of alkyl halides with alkenes leading to Heck-type and addition products is summarized. The development of Heck reaction with aliphatic halides although has made significant progress in the past decade and particularly recently, it was much less explored in comparison with the aryl halides. The use of Ni- and Co-catalyzed protocols allowed efficient Heck coupling of activated and unactivated alkenes with 1º , 2º and 3º alkyl halides. In addition, radical conjugate addition to activated alkenes has become a well-established method that has led to efficient construction of many natural products. The utilization of Ni- and Co-catalyzed strategies would avoid toxic tin reagents, and therefore worth exploring. The recent development of Ni- and Co-catalyzed addition of alkyl halides to alkenes displays much improved reactivity and functional group tolerance. In this mini-review, we also attempt to overview the mechanisms that are proposed in the reactions, aiming at providing insight into the nickel and cobalt-catalyzed coupling of alkyl halides with alkenes.

Upon irradiation with near-UV or visible light, organic diselenides undergo homolytic cleavage of their selenium-selenium linkage to generate the corresponding seleno radicals, which can add to alkynes, allenes, and related unsaturated compounds. In the case of alkynes, vicinally diselenated alkenes are synthesized successfully. Photoinduced bisselenation of allenes takes place selectively at the terminal double bond of allenes. In sharp contrast, photoinduced addition of organic diselenides to alkenes is an inefficient process. However, combination of diselenides and disulfides under photoirradiation conditions results in highly regioselective thioselenation of alkenes based on the higher reactivity of thio radicals toward alkenes and the higher carbon radical capturing ability of diselenides. Similar conditions can be employed with a variety of unsaturated compounds such as alkynes, allenes, conjugated dienes, vinylcyclopropanes, and isocyanides. This protocol can also be applied to selenotelluration, selenophosphination, and perfluoroalkylselenation of unsaturated compounds. The excellent carbon radical capturing ability of diselenides makes it possible to attain sequential addition of diselenides to several unsaturated compounds by suppression of polymerization of unsaturated compounds. When the sequential addition takes place intramolecularly under photoirradiation conditions, cyclic products are obtained successfully via a radical cyclization process. In addition, novel photoinduced electrocyclic reaction of o-alkynylaryl isocyanides with diselenides efficiently affords diselenated quinoline derivatives.

Organophosphorus compounds are of high importance in organic synthesis, catalysis, biochemistry, pharmaceuticals, and material science. In this mini review, we summarize our recent studies on transition metal-catalyzed green and atom efficient transformations of P(O)-H bonds to various versatile organophosphorus compounds, including the highly regio- and stereoselective P(O)-H additions to carbon-carbon unsaturated compounds, asymmetric hydrophosphorylation reactions, and dehydrogenative coupling reactions of P(O)-H compounds with carbon-H and heteroatom-H compounds. These new reactions provide efficient, general and practical ways for the preparation of a variety of well-defined functional organophosphorus compounds. Mechanistic aspects related to the catalytic processes are also discussed.

Nucleophilic phosphine catalysis has proven to be a practical and powerful synthetic strategy in organic chemistry, which can provide easy access to five-, six-, seven-, and eight-membered nitrogen heterocyclic compounds. The reaction topologies can be controlled by a proper choice of the phosphine catalysts, as well as the functionalization of the reaction substrates. In many cases, the reactions take place smoothly at room temperature, with high efficiency and atom economy. This mini-review presents the recent advances in nucleophilic phosphine catalysis for the synthesis of drug-like nitrogen heterocylic compounds. The nitrogen heterocyclic compounds with significant biological activities derived from the library based on nucleophilic phosphine-catalyzed annulation reactions are also highlighted.

The γ-butenolide structural motif is a prominent feature in many bioactive natural products and drugs. This short review summarizes catalytic asymmetric synthesis of γ-butenolides through direct vinylogous reactions by metal complexes and organocatalysts. In light of building chiral γ-tertiary and quaternary carbon centers of butenolides, three synthetic strategies are included: 1) the reactions with furanone derivatives as nucleophiles, 2) olefination of γ,γ- disubstituted butenolides and 3) the reactions by using γ,γ-disubstituted butenolides as nucleophiles.

Heterocyclic compounds are of high importance in constructing active drug intermediates library. The emergence of solid-phase and combinatorial chemistry has led to renewed interest in using organoselenium resins to library drug-like production. In this mini review, we summarize the construction of heterocyclic compounds libraries such as isoxazoles, oxadiazoles, triazoles, pyrimidines, pyrrolines, indolines, benzopyrans, furans etc. using organoselenium resins. And it provided efficient and practical ways for the preparation of a variety of well-defined functional heterocyclic compounds with the advantages of good yields, high purity, straightforward operations, broad range and high diversity of the products, lack of odor, and good stability of the resins, all of these give expression to green chemistry.

Alzheimer's disease (AD) is one of the most threatening diseases affecting the aged with high incidence. Though AD has been defined for more than 100 years, it is still incurable. The drugs clinically used for the treatment of this disease, such as acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonist, can only provide a limited therapeutic effect. The need of effective drugs has stimulated the search for new compounds with potential clinical utility. Natural products are rich and unexplored sources for discovering novel leading compounds. Currently, a great number of natural products have been found possessing anti-AD property counteracting different etiological factors of AD. This review will give an update demonstration on the novel anti-AD natural products and their derivatives/analogues, which have been divided into five subgroups according to their different action mechanisms: AChEIs, antioxidants, neuroprotective agents, monoamine oxidase (MAO) inhibitors, and tau hyperphosphorylation inhibitors. We put special emphasis on the findings in the past 5 years. Besides, the drug design strategy as well as the structure-activity relationship of the relevant compounds is also discussed when it is possible.

Diabetes mellitus is a chronic progressive metabolic disorder that has profound consequences for individuals, families, and society. To date, main available oral antidiabetic medications target either insulin resistance (metformin, glitazones), or insulin deficiency (sulfonylureas, glinides), but leading to shortfalls in medication. Advancement in modern oral hypoglycemic agents may be encouraged with or in place of traditional therapies. The lower risk for hypoglycemic events as compared with other insulinotropic or insulin-sensitizing agents make DPP-4 inhibitors very promising candidates for a more physiological treatment of type-2 diabetes. Only some DPP-4 inhibitors are currently used for the treatment of type 2 diabetes (T2DM) and various inhibitors currently undergoing animal and human testing. A number of catalytically active DPPs distinct from DPP-4 (DPP II, FAP, DPP-8, and DPP-9) have been described that is associated with side-effect and toxicity. To discover potent and selective and safer drugs in a shorter time frame and with reduced cost it requires using an innovative approach for designing novel inhibitors. This review article focuses on the status of advanced lead candidates of DPP group and their binding affinity with the active site residue of target structure which help in discovery of potent and selective DPP-4 inhibitors by lead optimization approach.

Cabazitaxel has recently been approved by FDA for the treatment of docetaxel resistant hormone-refractory prostate cancer. It has been developed by Sanofi-Aventis under the trade name of Jevtana. It is given in combination with prednisone/prednisolone and has passed the clinical trial over well-known drug mitoxantrone. This drug is a microtubule depolymerization inhibitor, which can penetrate blood brain barrier (BBB). The FDA granted fast track designation to this drug in November 2009 and thereafter, new drug application submission was done in March 2010. Priority review to this drug was granted in April 2010 and finally in July 2010 it was approved by FDA. It is available in the form of injection in the dose of 60 mg/1.5 mL, which should be diluted prior to its use by the diluents supplied along with the injection. It is a second-line drug and has proven to be effective in patients experiencing docetaxel based treatment failure.

Pyrazoline is an important five membered nitrogen heterocycle, which has been extensively researched upon. The ring is quite stable and has inspired chemists to carry out various structural variations in the ring. This has propelled the development of distinct pyrazolines with an array of pharmacological activities viz. anti-inflammatory, analgesic, antimicrobial, anticancer, antidepressant etc. The review aims at highlighting this pharmacological diversity of pyrazolines. The review is a gist of latest work done describing the pharmacological aspects and potential of pyrazoline ring.