Antitumor active trans‑platinum complexes through metabolic stability and enhanced cellular accumulation.

Utilizing isoquinoline as a carrier ligand, we have evaluated the reactivity of selected trans‑platinum planar amine (TPA) carboxylate compounds by varying the leaving carboxylate group (acetate, hydroxyacetate, and lactate) in an effort to optimize the cytotoxic and metabolic efficiency. To measure the pharmacological properties of these compounds, a combination of systematic biophysical and biological studies were carried out mainly involving substitution reaction with NAM (N-acetyl-methionine), effects on DNA structural perturbation, cytotoxicity, cellular accumulation, metabolic stability, and cell cycle effects. TPA compounds showed minimal losses in cytotoxic efficacy and outperformed cisplatin after pre-incubation with serum, while displaying a distinct micromolar cytotoxic activity with minimal DNA binding and unaltered cell cycle.

A Comparison of Di- and Trinuclear Platinum Complexes Interacting with Glycosaminoglycans for Targeted Chemotherapy.

Heparan sulfate proteoglycans (HSPGs) and their associated proteins aid in tumor progression through modulation of biological events such as cell invasion, angiogenesis, metastasis, and immunological responses. Metalloshielding of the anionic heparan sulfate (HS) chains by cationic polynuclear platinum complexes (PPCs) prevents the HS from interacting with HS-associated proteins and thus diminishes the critical functions of HSPG. Studies herein exploring the PPC-HS interactions demonstrated that a series of PPCs varying in charge, nuclearity, distance between Pt centers, and hydrogen-bonding ability influence HS affinity.

Exploitation of Sulfated Glycosaminoglycan Status for Precision Medicine of Triplatin in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers. TNBC is known to be most aggressive and when metastatic is often drug-resistant and uncurable. Biomarkers predicting response to therapy improve treatment decisions and allow personalized approaches for patients with TNBC.

Conformational Modulation of Iduronic Acid-Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs.

H NMR spectroscopic studies on the 1:1 adduct of the pentasaccharide Fondaparinux (FPX) and the substitution-inert polynuclear platinum complex TriplatinNC show significant modulation of geometry around the glycosidic linkages of the FPX constituent monosaccharides. FPX is a valid model for the highly sulfated cell signalling molecule heparan sulfate (HS). The conformational ratio of the C : S forms of the FPX residue IdoA(2S) is altered from ca.

Substitution-Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate.

Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumour-related events including angiogenesis, cell invasion, and metastasis. Metalloshielding of heparan sulfate (HS) by positively charged polynuclear platinum complexes (PPCs) effectively inhibits physiologically critical HS functions. Studies using bacterial P.

Comparison of Metal-Ammine Compounds Binding to DNA and Heparin. Glycans as Ligands in Bioinorganic Chemistry.

We present spectroscopic and biophysical approaches to examine the affinity of metal-ammine coordination complexes for heparin as a model for heparan sulfate (HS). Similar to nucleic acids, the highly anionic nature of heparin means it is associated in vivo with physiologically relevant cations, and this work extends their bioinorganic chemistry to substitution-inert metal-ammine compounds (M). Both indirect and direct assays were developed.

Antiangiogenic platinum through glycan targeting.

Heparan sulfate is identified as a ligand receptor for polynuclear platinum anti-cancer agents through sulfate cluster binding. We present a new biological role for platinum and coordination compounds and a new target for metal-based drugs while presenting a new chemotype for heparanase and growth factor inhibition through modulation (metalloshielding) of their interactions. Masking of extracellular (ECM)-resident heparan sulfate (HS) through metalloshielding results in very effective inhibition of physiologically critical HS functions including enzyme (heparanase, HPSE) and protein growth factor recognition.