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. Biochemical mechanisms of action, medicinal chemistry SAR studies, and numerous X-ray cocrystal structures are analyzed to identify the precise role of the methoxy group for many of the drugs and drug classes. Although the methoxy substituent can be considered as the hybridization of a hydroxy and a methyl group, the combination of these functionalities often results in unique effects that can amount to more than the sum of the individual parts.

"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. Following the literature terminology of the "magic methyl effect" in drugs, the term "magic chloro effect" has been coined herein. Although reports of 500-fold or 1000-fold potency improvements are often serendipitous discoveries that can be considered "magical" rather than planned, hypotheses made to explain the magic chloro effect can lead to lessons that accelerate the cycle of drug discovery.

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. The final two sp3 C-H oxidations at C1 and C7 were attained by dioxirane-mediated C-H oxidation and an oxidation relay based on judicious substrate design, culminating in a two-phase synthesis of Taxol. The purpose of this Perspective is to articulate strategies and tactics developed for the two-phase synthesis of taxanes, whose lessons can be potentially extrapolated to medicinal chemistry endeavors in the taxane family, as well as to the synthesis of other terpene families.

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

The Stigonemataceae 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. However, academic and industrial interests were not always aligned, and therefore the investment has become increasingly difficult to justify from industry's point of view. With fluctuating macroeconomic factors, this type of unrestricted grant has become more rare and has been largely replaced by smaller and more focused partnerships. In our view, forging a partnership with industry can be a golden opportunity for both parties and can represent a true symbiosis. This type of project-specific collaboration is engendered by industry's desire to access very specific academic expertise that is required for the development of new technologies at the forefront of science. Since financial pressures do not allow companies to spend the time to acquire this expertise and even less to explore fundamental research, partnering with an academic laboratory whose research is related to the problem gives them a viable alternative. From an academic standpoint, it represents the perfect occasion to apply "pure science" research concepts to solve problems that benefit humanity. Moreover, it offers a unique opportunity for students to face challenges from the "real world" at an early stage of their career. Although not every problem in industry can be solved by research developments in academia, we argue that there is significant scientific overlap between these two seemingly disparate groups, thereby presenting an opportunity for a symbiosis. This type of partnership is challenging but can be a win-win situation if both parties agree on some general guidelines, including clearly defined goals and deliverables, biweekly meetings to track research progress, and quarterly or annual meetings to recognize overarching, common objectives. This Account summarizes our personal experience concerning collaborations with various industrial groups and the way it impacted the research programs for both sides in a symbiotic fashion.

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. This intermediate can then be desulfonylated to the methylated product or elaborated to a deuteriomethylated product, and can divergently access medicinally important motifs. This mild, operationally simple protocol that can be conducted in open air at room temperature is compatible with sensitive functional groups for the late-stage functionalization of pharmacologically relevant substrates.

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. This product was then modified further to give (+)-taxadiene, the lowest oxidized member of the taxane family of natural products.

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. Although the synthesis of the zinc sulfinate salts can generally be completed within 3 h, workup can take up to 24 h and purification can take up to 3 h. Following the steps in this protocol would enable the user to generate a small toolkit of zinc sulfinate reagents over the course of 1 week.

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. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.

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). Therefore, it may be of use to distinguish between what, in our view, are two distinct categories of C-H functionalization logic: "guided" and "innate". Guided C-H functionalizations, as the name implies, are guided by external reagents or directing groups (covalently or fleetingly bound) to install new functional groups at the expense of specifically targeted C-H bonds. Conversely, innate C-H functionalizations may be broadly defined as reactions that exchange C-H bonds for new functional groups based solely on natural reactivity patterns in the absence of other directing forces. Two substrates that illustrate this distinction are dihydrojunenol and isonicotinic acid. The C-H functionalization processes of hydroxylation or arylation, respectively, can take place at multiple locations on each molecule. Innate functionalizations lead to substitution patterns that are dictated by the inherent bias (steric or electronic) of the substrate undergoing C-H cleavage, whereas guided functionalizations lead to substitution patterns that are controlled by external directing forces such as metal complexation or steric bias of the reagent. Although the distinction between guided and innate C-H functionalizations may not always be clear in cases that do not fit neatly into a single category, it is a useful convention to consider when analyzing reactivity patterns and strategies for synthesis. We must emphasize that although a completely rigorous distinction between guided and innate C-H functionalization may not be practical, we have nonetheless found it to be a useful tool at the planning stage of synthesis. In this Account, we trace our own studies in the area of C-H functionalization in synthesis through the lens of "guided" and "innate" descriptors. We show how harnessing innate reactivity can be beneficial for achieving unique bond constructions between heterocycles and carbonyl compounds, enabling rapid and scalable total syntheses. Guided and innate functionalizations were used synergistically to create an entire family of terpenes in a controlled fashion. We continue with a discussion of the synthesis of complex alkaloids with high nitrogen content, which required the invention of a uniquely chemoselective innate C-H functionalization protocol. These findings led us to develop a series of innate C-H functionalization reactions for forging C-C bonds of interest to the largest body of practicing organic chemists: medicinal chemists. Strategic use of C-H functionalization logic can have a dramatically positive effect on the efficiency of synthesis, whether guided or innate.

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. Patient demographics, injury mechanism, injury pattern, type of repair, and outcome were investigated. These data were analyzed to reveal tendencies in management, which were then organized into an algorithm. RESULTS: Twenty articles fit our criteria for a total of 91 tendons. Cases were mostly males involved in work accidents. Treatment options were tendon resection, reattachment to muscle, tendon transfer, and side-to-side repair. When the digit was replanted, tendons avulsed through avulsion amputations were preferentially treated by reattachment in the case of the thumb, transfers for the index and long fingers, and resection for the ring and small fingers. Reattachment was favored for metacarpophalangeal level amputations, while transfer was selected for proximal phalanx levels. For closed avulsion injuries, flexors were preferentially treated with reattachment or transfer, while extensors underwent transfer or side-to-side repair. CONCLUSIONS: In the management of tendon avulsions at the musculotendinous junction, specific procedures are favored depending on the mechanism of injury, the type of tendon and digit involved, and the level of bone amputation. An algorithm is presented to facilitate optimal treatment based on these injury characteristics.

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. The characteristic 6-8-6 tricyclic system of the taxane family, containing a bridgehead alkene, is forged via a vicinal difunctionalization/Diels-Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed through substrate control. This study lays a critical foundation for a planned access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself.

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. The syntheses are also characterized by an adherence to the concept of "redox economy". Analogous to "atom economy" or "step economy", "redox economy" minimizes the superfluous redox manipulations within a synthesis; rather, the oxidation state of intermediates linearly and steadily increases throughout the course of the synthesis.

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. On the other hand, addition of a small DAP-containing guest does not break the aggregates, but instead, results in new micelles which show a different selectivity profile from the parent morphology. We have examined the effect of a number of structural features in the block copolymers, on both the extent and selectivity of their macroscopic response to guests (that is, opening of the micelle). This study has resulted in a set of structural guidelines, which help in the design of effective molecule-responsive micelles for applications in selective drug delivery, sensing, and surface patterning.

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. We further investigated the IgE reactivity of the wheat protein hydrolysates using the inhibition ELISA method and sera of 5 patients sensitive to wheat. RESULTS: The wheat protein enzymatic hydrolysate samples showed high concentrations of peptides with molecular masses greater than 1,050 Da, whereas in contrast, the wheat protein acid hydrolysates showed extremely low concentrations of peptides with molecular masses greater than 1,050 Da. Tested wheat protein acid hydrolysates hardly inhibited the patient IgE binding ability to wheat proteins in the five patient sera. On the contrary, some tested wheat protein enzymatic hydrolysate samples inhibited the IgE binding ability to wheat proteins. CONCLUSION: These results suggested that the uptake of wheat protein enzymatic hydrolysates might still have the possibility of causing food allergic reactions in patients allergic to wheat and the processed foods containing them.

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. Among these regions, we focused on the pontine nuclei, the origin of the pontocerebellar mossy fibres, projecting mainly into the central region of the cerebellar cortex. The results of histological analysis showed that by P9 the number of neurons in the nuclei was reduced in the mutant to about one half and by P18 to one third of those in the wild type, whereas until P7 the number were about the same in wild-type and weaver mutant mice. Three-dimensional reconstruction of the nuclei showed a marked reduction in volume and shape of the mutant nuclei, correlating well with the decrease in neuronal number. In addition, DiI (a lipophilic tracer dye) tracing experiments revealed retraction of pontocerebellar mossy fibres from the cerebellar cortex after P5. From these results, we conclude that projecting neurons in the pontine nuclei, as well as cerebellar granule cells and dopaminergic neurons in substantia nigra, strongly degenerate in weaver mutant mice, resulting in elimination of pontocerebellar mossy fibres during cerebellar development.

[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. RESULTS: 1. Averaged out-of-pocket medical care costs for RA patients was estimated at yen 25,225 ($253.5) per person-month in 1994, in which direct medical care costs accounted for 53.9% and indirect medical care costs accounted for 46.1% of the total. Averaged substantial direct medical care costs including the costs covered by the public health insurance in addition to out-of-pocket costs was estimated at yen 512,000 ($5,140) per person-year based on the averaged 11.8% self-pay rate of the public health insurance in 1994. 2. The distribution curve of the total out-of-pocket medical care costs was highly skewed. Averaged total medical care costs in the 90th, 95th, and 100th percentiles were 4.5, 8.1, and 48 times as large as those in the median percentile, respectively. 3. Out-of-pocket direct medical care costs totaled in the top 1 and 5 percentiles reached 26.6%, and 57.6% of those in whole patients, respectively. 4. Variables most strongly related to the total out-of-pocket medical care costs were work disability in AIMS health status scales, followed by physical disability, rate of functional decline, pain, affect, daily dose of oral prednisolone, global assessment by physician, joint counts, blood levels of CRP, ESR, grip strength, blood concentrations of hemoglobin, age, Steinbrocker's class, sex, and medications, in this order. 5. There was a trend of increase in number of cases of male, middle aged, with lower levels of formal education and annual income, longer disease duration of 20 years or more, and single (male) or separated (female) in marital status, as the total out-of-pocket medical care costs increased. 6. The average rate of missed days due to illness to whole working days of RA patients was estimated at 21.9%. With increase in the rate of missed days, the annual income of RA patients decreased, indicating that the lower annual income of RA patents possibly resulted from their work disabilities. Based on the rate of missed days, the average earning loss due to the illness in RA patients was estimated approximately at yen 650,000 ($6,540) perperson-year, which was equivalent to 1.3 times the average direct medical care costs for RA per person-year. CONCLUSION: The costs of RA were strongly related to work disability and other health status as represented by AIMS-HRQOL scores. A small number of patents severely disabled shared a disproportionately large part of medical care costs. To reduce the costs, the measures to prevent the development of disability are most important.