Metal-Mediated, Autolytic Amide Bond Cleavage: A Strategy for the Selective, Metal Complexation-Catalyzed, Controlled Release of Metallodrugs.

Activation of metalloprodrugs or prodrug activation using transition metal catalysts represents emerging strategies for drug development; however, they are frequently hampered by poor spatiotemporal control and limited catalytic turnover. Here, we demonstrate that metal complex-mediated, autolytic release of active metallodrugs can be successfully employed to prepare clinical grade (radio-)pharmaceuticals. Optimization of the Lewis-acidic metal ion, chelate, amino acid linker, and biological targeting vector provides means to release peptide-based (radio-)metallopharmaceuticals in solution and from the solid phase using metal-mediated, autolytic amide bond cleavage (MMAAC). Our findings indicate that coordinative polarization of an amide bond by strong, trivalent Lewis acids such as Ga3+ and Sc3+ adjacent to serine results in the N, O acyl shift and hydrolysis of the corresponding ester without dissociation of the corresponding metal complex. Compound [68Ga]Ga-10, incorporating a cleavable and noncleavable functionalization, was used to demonstrate that only the amide bond-adjacent serine effectively triggered hydrolysis in solution and from the solid phase. The corresponding solid-phase released compound [68Ga]Ga-8 demonstrated superior in vivo performance in a mouse tumor model compared to [68Ga]Ga-8 produced using conventional, solution-phase radiolabeling. A second proof-of-concept system, [67Ga]Ga-17A (serine-linked) and [67Ga]Ga-17B (glycine-linked) binding to serum albumin via the incorporated ibuprofen moiety, was also synthesized. These constructs demonstrated that complete hydrolysis of the corresponding [68Ga]Ga-NOTA complex from [67Ga]Ga-17A can be achieved in naïve mice within 12 h, as traceable in urine and blood metabolites. The glycine-linked control [68Ga]Ga-17B remained intact. Conclusively, MMAAC provides an attractive tool for selective, thermal, and metal ion-mediated control of metallodrug activation compatible with biological conditions.

Radiometallation and photo-triggered release of ready-to-inject radiopharmaceuticals from the solid phase.

The efficient, large-scale synthesis of radiometallated radiopharmaceuticals represents an emerging clinical need which, to date, is inherently limited by time consuming, sequential procedures to conduct isotope separation, radiochemical labeling and purification prior to formulation for injection into the patient. In this work, we demonstrate that a solid-phase based, concerted separation and radiosynthesis strategy followed by photochemical release of radiotracer in biocompatible solvents can be employed to prepare ready-to-inject, clinical grade radiopharmaceuticals. Optimization of resin base, resin loading, and radiochemical labeling capacity are demonstrated with 67Ga and 64Cu radioisotopes using a short model peptide sequence and further validated using two peptide-based radiopharmaceuticals with clinical relevance, targeting the gastrin-releasing peptide and the prostate specific membrane antigen. We also demonstrate that the solid-phase approach enables separation of non-radioactive carrier ions Zn2+ and Ni2+ present at 105-fold excess over 67Ga and 64Cu by taking advantage of the superior Ga3+ and Cu2+ binding affinity of the solid-phase appended, chelator-functionalized peptide. Finally, a proof of concept radiolabeling and subsequent preclinical PET-CT study with the clinically employed positron emitter 68Ga successfully exemplifies that Solid Phase Radiometallation Photorelease (SPRP) allows the streamlined preparation of radiometallated radiopharmaceuticals by concerted, selective radiometal ion capture, radiolabeling and photorelease.

Synthesis and Conformational Properties of the Sterically Crowded D3d -Symmetric all-trans Hexa(spirotetrahydrofuranyl)cyclohexane System.

An unprecedented high barrier to ring inversion [Eq. (1)] prevents 1 from engaging in bifacial complexation with lithium ions. The X-ray crystal structure analysis of this hexaspiro compound corroborates the adoption of a cyclohexane chair with all six C-O bonds projected equatorially (1-eq).

A practical synthesis of 2-((1H-pyrrolo[2,3-b]pyridine-4-yl)methylamino)-5- fluoronicotinic acid.

A practical synthesis of a key pharmaceutical intermediate, 2-[(1H-pyrrolo[2,3-b]pyridine-4-yl)methylamino]-5-fluoronicotinic acid (1), is described. To introduce the aminomethyl moiety of 2 via a palladium-catalyzed cyanation/reduction sequence, a regioselective chlorination of 7-azaindole via the N-oxide was developed. A highly selective monodechlorination of 2,6-dichloro-5-fluoronicotinic acid was discovered to afford the nicotinic acid 3. The two building blocks 2 and 3 were then coupled to complete the preparation of 1.

N-Aryl-gamma-lactams as integrin alphavbeta3 antagonists.

Novel alphavbeta3 antagonists based on the N-aryl-gamma-lactam scaffold were prepared. SAR studies led to the identification of potent antagonists for alphavbeta3 receptor with excellent selectivity against the structurally related alpha(IIb)beta3 receptor. Additional interactions of N-aryl-gamma-lactam derivatives with alphavbeta3 were found when compared to c(-RGDf[NMe]V-) peptide antagonist. The effects of the conformation and configuration of the gamma-lactam core on the binding were also assessed.