Jon T. Njardarson

Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals

Nitrogen heterocycles are among the most significant structural components of pharmaceuticals. Analysis of our database of U.S. FDA approved drugs reveals that 59% of unique small-molecule drugs contain a nitrogen heterocycle. In this review we report on the top 25 most commonly utilized nitrogen heterocycles found in pharmaceuticals. The main part of our analysis is divided into seven sections: (1) three- and four-membered heterocycles, (2) five-, (3) six-, and (4) seven- and eight-membered heterocycles, as well as (5) fused, (6) bridged bicyclic, and (7) macrocyclic nitrogen heterocycles. Each section reveals the top nitrogen heterocyclic structures and their relative impact for that ring type. For the most commonly used nitrogen heterocycles, we report detailed substitution patterns, highlight common architectural cores, and discuss unusual or rare structures.

Tumor Targeting with Antibody-Functionalized, Radiolabeled Carbon Nanotubes

Single-walled carbon nanotubes (CNT) are mechanically robust graphene cylinders with a high aspect ratio that are comprised of sp2-bonded carbon atoms and possessing highly regular structures with defined periodicity. CNT exhibit unique mechanochemical properties that can be exploited for the development of novel drug delivery platforms. We hypothesized that novel prototype nanostructures consisting of biologics, radionuclides, fluorochromes, and CNT could be synthesized and designed to target tumor cells. Methods: Tumor-targeting CNT constructs were synthesized from sidewall-functionalized, water-soluble CNT platforms by covalently attaching multiple copies of tumor-specific monoclonal antibodies, radiometal-ion chelates, and fluorescent probes. The constructs were characterized spectroscopically, chromatographically, and electrophoretically. The specific reactivity of these constructs was evaluated in vitro by flow cytometry and cell-based immunoreactivity assays and in vivo using biodistribution in a murine xenograft model of lymphoma. Results: A soluble, reactive CNT platform was used as the starting point to build multifunctional constructs with appended antibody, metal-ion chelate, and fluorescent chromophore moieties to effect specific targeting, to carry and deliver a radiometal-ion, and to report location, respectively. These nanoconstructs were found to be specifically reactive with the human cancer cells they were designed to target in vivo in a model of disseminated human lymphoma and in vitro by flow cytometry and cell-based immunoreactivity assays versus appropriate controls. Conclusion: The key achievement in these studies was the selective targeting of tumor in vitro and in vivo by the use of specific antibodies appended to a soluble, nanoscale CNT construct. The ability to specifically target tumor with prototype-radiolabeled or fluorescent-labeled, antibody-appended CNT constructs was encouraging and suggested further investigation of CNT as a novel delivery platform.

Data-Mining for Sulfur and Fluorine: An Evaluation of Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery

Among carbon, hydrogen, oxygen, and nitrogen, sulfur and fluorine are both leading constituents of the pharmaceuticals that comprise our medicinal history. In efforts to stimulate the minds of both the general public and expert scientist, statistics were collected from the trends associated with therapeutics spanning 12 disease categories (a total of 1969 drugs) from our new graphical montage compilation: disease focused pharmaceuticals posters. Each poster is a vibrant display of a collection of pharmaceuticals (including structural image, Food and Drug Administration (FDA) approval date, international nonproprietary name (INN), initial market name, and a color-coded subclass of function) organized chronologically and classified according to an association with a particular clinical indication. Specifically, the evolution and structural diversity of sulfur and the popular integration of fluorine into drugs introduced over the past 50 years are evaluated. The presented qualitative conclusions in this article aim to promote innovative insights into drug development.

PET Imaging of Soluble Yttrium-86-Labeled Carbon Nanotubes in Mice

Background The potential medical applications of nanomaterials are shaping the landscape of the nanobiotechnology field and driving it forward. A key factor in determining the suitability of these nanomaterials must be how they interface with biological systems. Single walled carbon nanotubes (CNT) are being investigated as platforms for the delivery of biological, radiological, and chemical payloads to target tissues. CNT are mechanically robust graphene cylinders comprised of sp2-bonded carbon atoms and possessing highly regular structures with defined periodicity. CNT exhibit unique mechanochemical properties that can be exploited for the development of novel drug delivery platforms. In order to evaluate the potential usefulness of this CNT scaffold, we undertook an imaging study to determine the tissue biodistribution and pharmacokinetics of prototypical DOTA-functionalized CNT labeled with yttrium-86 and indium-111 (86Y-CNT and 111In-CNT, respectively) in a mouse model. Methodology and Principal Findings The 86Y-CNT construct was synthesized from amine-functionalized, water-soluble CNT by covalently attaching multiple copies of DOTA chelates and then radiolabeling with the positron-emitting metal-ion, yttrium-86. A gamma-emitting 111In-CNT construct was similarly prepared and purified. The constructs were characterized spectroscopically, microscopically, and chromatographically. The whole-body distribution and clearance of yttrium-86 was characterized at 3 and 24 hours post-injection using positron emission tomography (PET). The yttrium-86 cleared the blood within 3 hours and distributed predominantly to the kidneys, liver, spleen and bone. Although the activity that accumulated in the kidney cleared with time, the whole-body clearance was slow. Differential uptake in these target tissues was observed following intraveneous or intraperitoneal injection. Conclusions The whole-body PET images indicated that the major sites of accumulation of activity resulting from the administration of 86Y-CNT were the kidney, liver, spleen, and to a much less extent the bone. Blood clearance was rapid and could be beneficial in the use of short-lived radionuclides in diagnostic applications.

Creative approaches towards the synthesis of 2,5-dihydro- furans, thiophenes, and pyrroles. One method does not fit all!

A single method is never sufficient, which is why there is a great need for developing many diverse and creative approaches towards every chemical substrate class. This statement is supported by the contents of this perspective in addition to providing the reader with a helpful synthetic roadmap for selecting a suitable method for the building blocks being discussed. Detailed in this review are eight different synthetic approaches that provide access to valuable 2,5-dihydro- furan, thiophene and pyrrole building blocks. Each approach is briefly presented and its limits discussed. The strengths and weaknesses of each approach are further highlighted with a graphical table summary at the end. This summary clearly drives home the point that for every chemical substrate class we need many good methods in order to provide access to every member of each class.

A Concise Ring-Expansion Route to the Compact Core of Platensimycin†

using a novel antibiotic assay approach. Characterization revealed a unique compact core connected to a highly oxygenated and unusual aromatic ring through a propionate tether. Platensimycin has a novel mechanism of action, inhibiting the b-ketoacyl-(acyl carrier protein) synthase (FabF) in the bacterial fatty acid synthetic pathway. Several new members of this class have since been reported. These differ only in functionalization of the carboxylate terminus. This attractive natural product target has also encouraged researchers to engineer strains to improve its production. Despite a flurry of synthetic activity, only two groups have completed the total syntheses of platensimycin (1). All other reported efforts have focused on constructing the platensimycin core 3. To highlight the diversity of these synthetic approaches we have chosen to emphasize the last bond formed to complete the platensimycin core as reported by each research group (Figure 2). Recently, a series of derivatives obtained by modifying platensimycin have been reported. Alternatively, several research groups have developed analogues of platensimycin, some of which were equipotent with the natural product. These results bode well for analogue approaches utilizing diverted total synthetic strategies. We envisioned a concise retrosynthetic plan for the total synthesis of platensimycin (Scheme 1). Platensic acid (2) was our immediate target as it serves later as the branch point for accessing all the other members of this natural product family. We proposed that 2 could be accessed from 4 by a retro-

Beyond C, H, O, and N! Analysis of the Elemental Composition of U.S. FDA Approved Drug Architectures

The diversity of elements among U.S. Food and Drug Administration (FDA) approved pharmaceuticals is analyzed and reported, with a focus on atoms other than carbon, hydrogen, oxygen, and nitrogen. Our analysis reveals that sulfur, chlorine, fluorine, and phosphorous represent about 90% of elemental substitutions, with sulfur being the fifth most used element followed closely by chlorine, then fluorine and finally phosphorous in the eighth place. The remaining 10% of substitutions are represented by 16 other elements of which bromine, iodine, and iron occur most frequently. The most detailed parts of our analysis are focused on chlorinated drugs as a function of approval date, disease condition, chlorine attachment, and structure. To better aid our chlorine drug analyses, a new poster showcasing the structures of chlorinated pharmaceuticals was created specifically for this study. Phosphorus, bromine, and iodine containing drugs are analyzed closely as well, followed by a discussion about other elements.

Ring Expansions of Vinyloxiranes, -thiiranes, and -aziridines: Synthetic Approaches, Challenges, and Catalytic Success Stories

Ring expansion reactions of strained vinylic heterocyclic substrates have attracted the attention of the synthetic community for decades. Strategic manipulations of these organic architectures enable access to many useful synthetic intermediates. This paper highlights various methods for the ring expansion of vinyloxiranes, -thiiranes, and -aziridines described in the literature from 1964 to 2013.

Lewis Acid Catalyzed [1,3]-Sigmatropic Rearrangement of Vinyl Aziridines

This paper details the copper-catalyzed ring expansion of vinyl aziridines to 3-pyrrolines. Broad substrate scope (24 examples) using tosyl- and phthalimide-protected vinyl aziridine substrates is observed. Cu(hfacac)2 was determined to be superior to all other catalysts tested.

Stereospecific Ring Expansion of Chiral Vinyl Aziridines

In this report, it is demonstrated that chiral vinyl aziridines can be stereospecifically ring expanded. This synthetic approach allows controlled access to chiral 2,5-cis- or 2,5-trans-3-pyrroline products from starting materials with the appropriate aziridine geometry. Twenty three ring expansion examples, most of which feature a stereospecific cyclization, are presented.