The importance of the “SEM” group, or the 2-(trimethylsilyl)ethoxymethyl group, as an N-protecting group for special class of pyrrolopyridazinones is reported. Our studies indicate that standard Boc protection on the nitrogen of a pyrrolopyridazinone results in significant decomposition during the incorporation of biaryl groups via Pd-catalyzed cross coupling reactions. However, on using the SEM group, the resulting cross coupling reaction gives excellent yields with no decomposition products, enabling the synthesis of a variety of compounds that were targeted for their antitumor activity.

Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an amino acid transporter recognition element was shown to augment anti-tumour efficacy vs. Raji cells. Amino acid conjugation also improves the pharmacodynamic properties of experimental MCT1/2 inhibitors.

Sempervirine and analogues were synthesized using a route featuring Sonogashira and Larock Pd-catalyzed reactions. Structure–activity relationships were investigated using three human cancer cell lines. 10-Fluorosempervirine is the most potently cytotoxic member of the family yet described.

A novel synthetic route to 1,3,5,7-tetrasubstituted pyrimido[4,5-d]pyrimidine-2,4-diones, of interest for potential antitumor activity, is reported. The route uses 1,3-disubstituted 6-amino uracils as starting materials. The key step is a hydrazine-induced cyclization reaction to form the fused pyrimidine ring. By choosing different uracils, acylation reagents, and alkylation reagents, substituents at N-1, N-3, C-5, and C-7 may be selectively varied to provide a structurally diverse set of compounds for biological evaluation.

A general synthetic approach to β-carboline-containing alkaloids was developed. Two consecutive palladium-mediated processes, a Sonagashira coupling and a Larock indole annulation reaction, are central to the method. The scope of the approach was investigated and found to be amenable for constructing a variety of biologically significant natural products and also for preparing substituted analogues for optimization and analysis of their biological properties.

Novel substituted pteridine-derived inhibitors of monocarboxylate transporter 1 (MCT1), an emerging target for cancer therapy, are reported. The activity of these compounds as inhibitors of lactate transport was confirmed using a 14C-lactate transport assay, and their potency against MCT1-expressing human tumor cells was established using MTT assays. The four most potent compounds showed substantial anticancer activity (EC50 37–150 nM) vs MCT1-expressing human Raji lymphoma cells.

A direct and scalable route to γ-keto-α,β-unsaturated esters, useful intermediates in medicinal chemistry and natural products synthesis, is reported. The key step involves the use of Grubbs’ second-generation olefin metathesis catalyst for cross-metathesis of alkyl acrylates and 2° allylic alcohols. The metathesis step is followed by oxidation to give the desired products in high yield on scales of up to 25 g.

Rho kinase (ROCK) is currently investigated as a target for various diseases such as glaucoma and spinal cord injury. Herein, we report the asymmetric synthesis of chroman 1, a highly potent ROCK inhibitor, and its analogs. The inhibitory properties of these compounds for ROCK-II and a selected set of highly homologous kinases are also discussed.

Rho kinase (ROCK) inhibitors are potential therapeutic agents to treat disorders such as hypertension, multiple sclerosis, cancers, and glaucoma. Here, we disclose the synthesis, optimization, biological evaluation of potent indole and 7-azaindole based ROCK inhibitors that have high potency on ROCK (IC50 = 1 nM) with 740-fold selectivity over PKA (47). Moreover, 47 showed very good DMPK properties making it a good candidate for further development. Finally, docking studies with a homology model of ROCK-II were performed to rationalize the binding mode of these compounds and showed the compounds bound in both orientations to take advantage to H-bonds with Lys-121 of ROCK-II.

Therapeutic interventions with Rho kinase (ROCK) inhibitors may effectively treat several disorders such as hypertension, stroke, cancer, and glaucoma. Herein we disclose the optimization and biological evaluation of potent novel ROCK inhibitors based on substituted indole and 7-azaindole core scaffolds. Substitutions on the indole C3 position and on the indole NH and/or amide NH positions all yielded potent and selective ROCK inhibitors (25, 42, and 50). Improvement of aqueous solubility and tailoring of in vitro and in vivo DMPK properties could be achieved through these substitutions.

Rho Kinase (ROCK) is a serine/threonine kinase whose inhibition could prove beneficial in numerous therapeutic areas. We have developed a promising class of ATP-competitive inhibitors based upon a benzimidazole scaffold, which show excellent potency toward ROCK (IC50 <10 nM). This report details the optimization of selectivity for ROCK over other related kinases such as Protein kinase A (PKA).