The role of the methoxy group in approved drugs.

The methoxy substituent is prevalent in natural products and, consequently, is present in many natural product-derived drugs. It has also been installed in modern drug molecules with no remnant of natural product features because medicinal chemists have been taking advantage of the benefits that this small functional group can bestow on ligand-target binding, physicochemical properties, and ADME parameters. Herein, over 230 methoxy-containing small-molecule drugs, as well as several fluoromethoxy-containing drugs, are presented from the vantage point of the methoxy group.

"Magic Chloro": Profound Effects of the Chlorine Atom in Drug Discovery.

Chlorine is one of the most common atoms present in small-molecule drugs beyond carbon, hydrogen, nitrogen, and oxygen. There are currently more than 250 FDA-approved chlorine-containing drugs, yet the beneficial effect of the chloro substituent has not yet been reviewed. The seemingly simple substitution of a hydrogen atom (R = H) with a chlorine atom (R = Cl) can result in remarkable improvements in potency of up to 100,000-fold and can lead to profound effects on pharmacokinetic parameters including clearance, half-life, and drug exposure in vivo.

Two-Phase Total Synthesis of Taxanes: Tactics and Strategies.

This Perspective goes into the fine details of our laboratory's quest to answer a longstanding fundamental question: Could any new approach to terpene synthesis, perhaps one patterned on biosynthesis, enable a divergent synthetic approach to the taxane family of natural products? We targeted Taxol, the flagship taxane, as the upper limit of chemical complexity and employed two-phase terpene synthesis logic as the guiding strategy. The first synthesis target was taxadiene, the lowest oxidized member of the taxane family, followed by three site-selective allylic oxidations at C5, C10, and C13, which led to the two-phase synthesis of taxuyunnanine D. Successful C9 oxidation enabled access to a wider range of taxanes, which was demonstrated by the two-phase synthesis of decinnamoyltaxinine E and taxabaccatin III.

Scalable Total Syntheses of (-)-Hapalindole U and (+)-Ambiguine H.

The family of cyanobacteria produces a class of biogenetically related indole natural products that include hapalindoles and ambiguines. In this full account, a practical route to the tetracyclic hapalindole family is presented by way of an eight-step, enantiospecific, protecting-group-free total synthesis of (-)-hapalindole U that features an oxidative indole-enolate coupling. With gram-scale access to hapalindole U, the first total synthesis of an ambiguine alkaloid, (+)-ambiguine H, was completed via an isonitrile-assisted prenylation of an indole followed by a photofragmentation cascade.

Academia-industry symbiosis in organic chemistry.

Collaboration between academia and industry is a growing phenomenon within the chemistry community. These sectors have long held strong ties since academia traditionally trains the future scientists of the corporate world, but the recent drastic decrease of public funding is motivating the academic world to seek more private grants. This concept of industrial "sponsoring" is not new, and in the past, some companies granted substantial amounts of money per annum to various academic institutions in exchange for prime access to all their scientific discoveries and inventions.

C-H methylation of heteroarenes inspired by radical SAM methyl transferase.

A practical C-H functionalization method for the methylation of heteroarenes is presented. Inspiration from Nature's methylating agent, S-adenosylmethionine (SAM), allowed for the design and development of zinc bis(phenylsulfonylmethanesulfinate), or PSMS. The action of PSMS on a heteroarene generates a (phenylsulfonyl)methylated intermediate that can be easily separated from unreacted starting material.

Bioconjugation by native chemical tagging of C-H bonds.

A general C-H functionalization method for the tagging of natural products and pharmaceuticals is described. An azide-containing sulfinate reagent allows the appendage of azidoalkyl chains onto heteroaromatics, the product of which can then be attached to a monoclonal antibody by a "click" reaction. This strategy expands the breadth of bioactive small molecules that can be linked to macromolecules in a manner that is beyond the scope of existing methods in bioconjugation to permit tagging of the "seemingly untaggable".

Total synthesis of taxane terpenes: cyclase phase.

A full account of synthetic efforts toward a lowly oxidized taxane framework is presented. A non-natural taxane, dubbed "taxadienone", was synthesized as our first entry into the taxane family of diterpenes. The final synthetic sequence illustrates a seven-step, gram-scale and enantioselective route to this tricyclic compound in 18% overall yield.

Management of digital tendon avulsion at the musculotendinous junction of the forearm: a systematic review.

Background: Tendon avulsion at the musculotendinous junction caused by digit avulsion amputation or closed injury is a challenging problem, for which the literature lacks definitive recommendations regarding treatment. We have provided a systematic review and developed an algorithm to delineate optimal management of this injury.

Methods: Two independent reviewers undertook a systematic review of the literature to identify articles discussing management of forearm tendons avulsed at their musculotendinous junction.

Preparation and purification of zinc sulfinate reagents for drug discovery.

The present protocol details the synthesis of zinc bis(alkanesulfinate)s that can be used as general reagents for the formation of radical species. The zinc sulfinates described herein are generated from the corresponding sulfonyl chlorides by treatment with zinc dust. The products may be used crude, or a simple purification procedure may be performed to minimize incorporation of water and zinc chloride.

Practical and innate carbon-hydrogen functionalization of heterocycles.

Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications--such as aqueous solubility and their ability to act as ligands--render them challenging substrates for direct chemical functionalization.

Scalable enantioselective total synthesis of taxanes.

Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which has a suitable functional handle with which to access more oxidized members of its family. This route enables a gram-scale preparation of the 'parent' taxane--taxadiene--which is the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form.

Innate and guided C-H functionalization logic.

The combustion of organic matter is perhaps the oldest and most common chemical transformation utilized by mankind. The generation of a C-O bond at the expense of a C-H bond during this process may be considered the most basic form of C-H functionalization. This illustrates the extreme generality of the term "C-H functionalization", because it can describe the conversion of literally any C-H bond into a C-X bond (X being anything except H).

Enantiospecific total synthesis of the hapalindoles, fischerindoles, and welwitindolinones via a redox economic approach.

Full details are provided for the total synthesis of several members of the hapalindole family of natural products, including hapalindole Q, 12-epi-hapalindole D, 12-epi-fischerindole U, 12-epi-fischerindole G, 12-epi-fischerindole I, and welwitindolinone A. Use of the recently developed direct indole coupling enabled an efficient, practical, scalable, and protecting-group-free synthesis of each of these natural products. The original biosynthetic proposal is reviewed, and a revised biosynthetic hypothesis is suggested, validated by the above syntheses.

Molecule-responsive block copolymer micelles.

Ring-opening metathesis polymerization was used to generate an ABC triblock copolymer, containing complementary diamidopyridine (DAP) and thymine (THY) outer blocks, which assembles into spherical aggregates held together by DAP-THY noncovalent interactions. Addition of THY-containing small guest molecules results in complete opening and deaggregation of the block copolymer micelle. This molecular recognition and macroscopic response shows high selectivity to the guest structure, and tolerates only a small amount of conformational mobility in the THY guest.

Profile analysis and immunoglobulin E reactivity of wheat protein hydrolysates.

Background: Wheat protein hydrolysates have been traditionally used as food additives and are now being used in cooking worldwide. There have been a few studies on the relationship between the molecular mass distribution and the immunoglobulin E (IgE) reactivity of the wheat protein hydrolysates.

Method: We analyzed the peptide profile of commercial wheat protein hydrolysate samples from enzymatic or acid hydrolysis of wheat protein using size exclusion chromatography.

Degeneration of pontine mossy fibres during cerebellar development in weaver mutant mice.

In weaver mutant mice, substitution of an amino acid residue in the pore region of GIRK2, a subtype of the G-protein-coupled inwardly rectifying K+ channel, changes the properties of the homomeric channel to produce a lethal depolarized state in cerebellar granule cells and dopaminergic neurons in substantia nigra. Degeneration of these types of neurons causes strong ataxia and Parkinsonian phenomena in the mutant mice, respectively. On the other hand, the mutant gene is also expressed in various other brain regions, in which the mutant may have effects on neuronal survival.

[A multicenter cross-sectional study on the health related quality of life of patients with rheumatoid arthritis using a revised Japanese version of the arthritis impact measurement scales version 2 (AIMS 2), focusing on the medical care costs and their associative factors].

Objective: To survey the actual conditions of medical care costs incurred by Japanese patients with rheumatoid arthritis, and to investigate impacts of health status, demographic and socioeconomic factors, clinical and laboratory measures, and medications on disease costs.

Methods: Self-reported health status questionnaires of the revised Japanese version of AIMS 2, and reports on out-of-pocket medical care costs were collected from 1471 patients with classical and definite rheumatoid arthritis recruited through the arthritis study group of Ministry of Public Health and Welfare consisting of eleven arthritis centers across the country during three months from September, 1994. Impacts of health status and other demographic and clinical factors on medical care costs were statistically analyzed by using chi-square tests for categorical variables and Spearman's rank correlation analysis for numerical variables.