Peptide Binder to Glypican-3 as a Theranostic Agent for Hepatocellular Carcinoma.

Glypican-3 (GPC3) is a membrane-associated glycoprotein that is significantly upregulated in hepatocellular carcinomas (HCC) with minimal to no expression in normal tissues. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for targeted radiopharmaceutical therapy to treat HCC, a leading cause of cancer-related deaths worldwide. Methods: DOTA-RYZ-GPC3 (RAYZ-8009) comprises a novel macrocyclic peptide binder to GPC3, a linker, and a chelator that can be complexed with different radioisotopes. The binding affinity was determined by surface plasma resonance and radioligand binding assays. Target-mediated cellular internalization was radiometrically measured at multiple time points. In vivo biodistribution, monotherapy, and combination treatments with 177Lu or 225Ac were performed on HCC xenografts. Results: RAYZ-8009 showed high binding affinity to GPC3 protein of human, mouse, canine, and cynomolgus monkey origins and no binding to other glypican family members. Potent cellular binding was confirmed in GPC3-positive HepG2 cells and was not affected by isotope switching. RAYZ-8009 achieved efficient internalization on binding to HepG2 cells. Biodistribution study of 177Lu-RAYZ-8009 showed sustained tumor uptake and fast renal clearance, with minimal or no uptake in other normal tissues. Tumor-specific uptake was also demonstrated in orthotopic HCC tumors, with no uptake in surrounding liver tissue. Therapeutically, significant and durable tumor regression and survival benefit were achieved with 177Lu- and 225Ac-labeled RAYZ-8009, as single agents and in combination with lenvatinib, in GPC3-positive HCC xenografts. Conclusion: Preclinical in vitro and in vivo data demonstrate the potential of RAYZ-8009 as a theranostic agent for the treatment of patients with GPC3-positive HCC.

RYZ101 (Ac-225 DOTATATE) Opportunity beyond Gastroenteropancreatic Neuroendocrine Tumors: Preclinical Efficacy in Small-Cell Lung Cancer.

Overexpression of somatostatin receptors (SSTR), particularly SSTR2, is found in gastroenteropancreatic neuroendocrine tumors (GEP-NET), and subsets of other solid tumors such as small-cell lung cancer (SCLC). SCLC accounts for approximately 13% to 15% of lung cancer and lacks effective therapeutic options. IHC analysis indicates that up to 50% of SCLC tumors are SSTR2-positive, with a substantial subset showing high and homogenous expression. Peptide receptor radionuclide therapy with radiolabeled somatostatin analogue, Lu-177 DOTATATE, has been approved for GEP-NETs. Different strategies aimed at improving outcomes, such as the use of alpha-emitting radioisotopes, are currently being investigated. RYZ101 (Ac-225 DOTATATE) is comprised of the alpha-emitting radioisotope actinium-225, chemical chelator DOTA, and octreotate (TATE), a somatostatin analogue. In the cell-based competitive radioligand binding assay, RAYZ-10001-La (lanthanum surrogate for RYZ101) showed high binding affinity (Ki = 0.057 nmol/L) to human SSTR2 and >600-fold selectivity against other SSTR subtypes. RAYZ-10001-La exhibited efficient internalization to SSTR2-positive cells. In multiple SSTR2-expressing SCLC xenograft models, single-dose intravenous RYZ101 3 µCi (0.111 MBq) or 4 µCi (0.148 MBq) significantly inhibited tumor growth, with deeper responses, including sustained regression, observed in the models with higher SSTR2 levels. The antitumor effect was further enhanced when RYZ101 was combined with carboplatin and etoposide at clinically relevant doses. In summary, RYZ101 is a highly potent, alpha-emitting radiopharmaceutical agent, and preclinical data demonstrate the potential of RYZ101 for the treatment of patients with SSTR-positive cancers.

pKa Scale for Cyclopropenium Ions with Applications in CO2 Capture.

Molecular acid-base properties are core to understanding chemical systems and the prediction of reactivity. This axiom holds for cyclopropenium ions in terms of their broad use as (organo)catalysts, ligands, redox-flow batteries, and applications in materials sciences. In view of this significant status, and with it, the critical importance of acidity, we disclose in this report the first comprehensive computational study of the pKa values of cyclopropenium ions employing a subset of 70 structurally diverse cyclopropenium derivatives, density functional computations, and Hammett linear free-energy relationships. Capitalizing upon these computed findings, and with an eye toward greenhouse gas trapping, we further document the timely use of a cyclopropenium-cyclopropenylidene coupled platform for CO2 capture and light-triggered release.

Trisaminocyclopropenium Cations as Small-Molecule Organic Fluorophores: Design Guidelines and Bioimaging Applications.

The discovery of fluorescence two centuries ago ushered in, what is today, an illuminating field of science rooted in the rational design of photochromic molecules for task-specific bio-, material-, and medical-driven applications. Today, this includes applications in bioimaging and diagnosis, photodynamic therapy regimes, in addition to photovoltaic devices and solar cells, among a vast multitude of other usages. In furthering this indispensable area of daily life and modern-day scientific research, we report herein the synthesis of a class of trisaminocyclopropenium fluorophores along with a systematic investigation of their unique molecular and electronic dependent photophysical properties. Among these fluorophores, tris[N(naphthalen-2-ylmethyl)phenylamino] cyclopropenium chloride (TNTPC) displayed a strong photophysical profile including a 0.92 quantum yield ascribed to intramolecular charge transfer and intramolecular through-space conjugation. Moreover, this cyclopropenium-based fluorophore functions as a competent imaging agent for DNA visualization and nuclear counterstaining in cell culture. To facilitate the broader use of these compounds, design principles supported by density functional theory calculations for engineering analogs of this class of fluorophores are offered. Collectively, this study adds to the burgeoning interest in cyclopropenium compounds and their unique properties as fluorophores with uses in bioimaging applications.

Development of an Unsymmetrical Cyclopropenimine-Guanidine Platform for Accessing Strongly Basic Proton Sponges and Boron-Difluoride Diaminonaphthalene Fluorophores.

An unsymmetrical guanidine-cyclopropenimine proton sponge DAGUN and the related BF2 -chelate DAGBO are reported. Insight into the structural, electronic, bonding and photophysical properties of these two molecules are presented. Joint experimental and theoretical studies reveal the protonated form of DAGUN possesses an intramolecular N⋅⋅⋅H-N hydrogen bond which affords a high experimental pKBH+ of 26.6 (computed=26.3). Photophysical studies show that in solution DAGUN displays a green emission at 534 nm, with a large Stokes shift of 235 nm (14,718 cm-1 ). In contrast, the conjugate acid DAGUN-H+ is only weakly emissive due to attenuated intramolecular charge transfer. X-ray diffraction studies reveal that DAGBO contains a stable tetracoordinate boronium cation, reminiscent of the well-established BODIPY family of dyes. In solution, DAGBO exhibits a strong blue emission at 450 nm coupled with a large Stokes shift (Δλ=158 nm, Δν=11,957 cm-1 ) and quantum yield of 62 %, upon excitation at 293 nm. DAGBO sets the stage as the first entry into a new class of boron-difluoride diaminonaphthalenes (BOFDANs) that represent highly fluorescent and tunable next-generation dyes with future promise for biosensing and bioimaging applications.

Mechanistic Insight toward Understanding the Role of Charge in Thiourea Organocatalysis.

Pyranylation and glycosylation are pivotal for accessing a myriad of natural products, pharmaceuticals, and drug candidates. Catalytic approaches for enabling these transformations are of utmost importance and integral to advancing this area of synthesis. In exploring this chemical space, a combined experimental and computational mechanistic study of pyranylation and 2-deoxygalactosylation catalyzed by a cationic thiourea organocatalyst is reported. To this end, a thiourea-cyclopropenium organocatalyst was employed as a model system in combination with an arsenal of mechanistic techniques, including 13C kinetic isotope effect experiments, deuterated labeling studies, variable-temperature 1H NMR spectroscopy, and density functional theory calculations. From these studies, two distinct reaction pathways were identified for this transformation corresponding to either dual hydrogen bond (H-bond) activation or Brønsted acid catalysis. The former involving thiourea orchestrated bifurcated hydrogen bonding proceeded in an asynchronous concerted fashion. In contrast, the latter stepwise mechanism involving Brønsted acid catalysis hinged upon the formation of an oxocarbenium intermediate accompanied by subsequent alcohol addition.

Fluorescence of Cyclopropenium Ion Derivatives.

The synthesis of cyclopropenium-substituted amino compounds and analysis of their photophysical properties is described. Systematic structural modifications of these derivatives lead to measurable and predictable changes in molar extinction coefficients, quantum yields, and Stokes shifts. Using time-dependent density functional theory (TD-DFT) calculations, the origin of these trends was traced to internal charge transfer (ICT) coupled with ensuing structural reorganization for select naphthalene functionalized derivatives. Associated with this structural reorganization was an inward gearing of the cyclopropenium ring and twisting of the peri-NMe2 group into coplanarity with the naphthalene ring system. Further, reinforcement of an intramolecular H-bond (IMHB) in the excited state of these derivatives alludes to the importance of photoinduced H-bonding in this new class of cyclopropenium based fluorophores.