Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared to those of the cross-linker. Thus, the improved in vivo tolerability and anti-tumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment.on May 9, 2018.

Despite impressive advances over the years, [1] there are still important transformations that lack catalytic asymmetric variants. While Lewis acid catalyzed additions of allylsilanes to carbonyl compounds [2] and acetals [3] have been well studied using catalytic, [4] as well as auxiliary-based methods to control absolute configuration, [5] to the best of our knowledge, there are no effective methods for catalyzing the asymmetric 1,4-addition of allyltrimethylsilane to unsaturated carbonyl compounds. [6] In that regard, we report herein a catalytic enantioselective conjugate addition of allyltrimethylsilane to various activated cyclic enones with selectivities surpassing 98 % ee. The 1,4-addition of the air-and moisture-stable nucleophile to unsaturated carbonyl compounds proceeds to > 95 % conversion in the presence of Cu(OTf) 2 (10 mol %) with the commercially available di(tert-butyl)bis(oxazoline) (box) ligand (2). [7] We show how these products can be functionalized to a variety of useful enantiomerically enriched systems.Our initial studies into the development of a chiral Lewis acid catalyst indicated that simple cyclic and acyclic a,bunsaturated carbonyls (ketones and esters) did not react with a variety of metal-ligand combinations.[8] We therefore sought to activate the substrate by installation of a second electron-withdrawing/chelating group at the a-position of the enone (i.e., 1). In the presence of Cu(OTf) 2 (7 mol %) and bis(oxazoline) ligand 2 (8 mol %) in Cl(CH 2 ) 2 Cl, we obtained the desired 1,4-allyl-addition product 3 in > 95 % conversion (after 30 min at 0 8C) and 72 % ee as a mixture of keto-enol tautomers (Scheme 1). Alternative solvents (CH 2 Cl 2 , Et 2 O, toluene, EtOAc, etc.) and metal salts, including other copper salts, resulted in lower selectivities.[9] Other chiral ligands (e.g., peptide-based, [10] salen, [11] Trost ligand [12] ) led to high conversion (> 95 %), but with low selectivity (< 5 % ee).To identify a more effective catalyst, we prepared and screened approximately 40 mono-and bis(oxazoline) ligands.

Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein–protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2–p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.

Antibody−drug conjugates have elicited great interest recently as targeted chemotherapies for cancer. Recent preclinical and clinical data have continued to raise questions about optimizing the design of these complex therapeutics. Biochemical methods for site-specific antibody conjugation have been a design feature of recent clinical ADCs, and preclinical reports suggest that site-specifically conjugated ADCs generically offer improved therapeutic indices (i.e., the fold difference between efficacious and maximum tolerated doses). Here we present the results of a systematic preclinical comparison of ADCs embodying the DNA-alkylating linker-payload DGN549 generated with both heterogeneous lysine-directed and site-specific cysteine-directed conjugation chemistries. Importantly, the catabolites generated by each ADC are the same regardless of the conjugation format. In two different model systems evaluated, the site-specific ADC showed a therapeutic index benefit. However, the therapeutic index benefit is different in each case: both show evidence of improved tolerability, though with different magnitudes, and in one case significant efficacy improvement is also observed. These results support our contention that conjugation chemistry of ADCs is best evaluated in the context of a particular antibody, target, and linker-payload, and ideally across multiple disease models.

The syntheses of two isoprostanyl phospholipids are described. A newly established route to 15-F(2t)-isoprostane and ent-15-epi-F(2t)-isoprostane has allowed for the selective preparation of 15-F(2t)-isoprostanyl phosphatidylethanolamine and ent-15-epi-F(2t)-isoprostanyl phosphatidylcholine. The nature of the headgroups dictates the coupling strategy used to attach the appropriately protected isoprostanes to the corresponding lysophospholipids. Preliminary 1H NMR and 31P NMR studies indicate that these isoprostanyl phospholipids aggregate in apolar solvents.