Isosteric Replacement of Sulfur to Selenium in a Thiosemicarbazone: Promotion of Zn(II) Complex Dissociation and Transmetalation to Augment Anticancer Efficacy

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(14), С. 12155 - 12183

Опубликована: Июль 5, 2024

We implemented isosteric replacement of sulfur to selenium in a novel thiosemicarbazone (PPTP4c4mT) create selenosemicarbazone (PPTP4c4mSe) that demonstrates potentiated anticancer efficacy and selectivity. Their design specifically incorporated cyclohexyl styryl moieties sterically inhibit the approach their Fe(III) complexes oxy-myoglobin heme plane. Importantly, contrast clinically trialed thiosemicarbazones Triapine, COTI-2, DpC, PPTP4c4mT PPTP4c4mSe did not induce detrimental oxidation. Furthermore, demonstrated more potent antiproliferative activity than homologous thiosemicarbazone, PPTP4c4mT, with selectivity being superior or similar, respectively, COTI-2. An advantageous property Zn(II) relative analogues was greater transmetalation Cu(II) lysosomes. This latter effect probably promoted activity. Both ligands down-regulated multiple key receptors display inter-receptor cooperation leads aggressive resistant breast cancer.

Язык: Английский

---

Targeting lysosomes by design: novel N-acridine thiosemicarbazones that enable direct detection of intracellular drug localization and overcome P-glycoprotein (Pgp)-mediated resistance

Chemical Science, Год журнала: 2024, Номер 15(37), С. 15109 - 15124

Опубликована: Янв. 1, 2024

Innovative

Язык: Английский

---

Differential transmetallation of complexes of the anti-cancer thiosemicarbazone, Dp4e4mT: effects on anti-proliferative efficacy, redox activity, oxy-myoglobin and oxy-hemoglobin oxidation

Chemical Science, Год журнала: 2023, Номер 15(3), С. 974 - 990

Опубликована: Дек. 15, 2023

The di-2-pyridylthiosemicarbazone (DpT) analogs demonstrate potent and selective anti-proliferative activity against human tumors. current investigation reports the synthesis chemical biological characterization of Fe(iii), Co(iii), Ni(ii), Cu(ii), Zn(ii), Ga(iii), Pd(ii) complexes promising second generation DpT analog, di-2-pyridylketone-4-ethyl-4-methyl-3-thiosemicarbazone (Dp4e4mT). These studies that Dp4e4mT display distinct

Язык: Английский

---

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(22), С. 15453 - 15476

Опубликована: Ноя. 3, 2023

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe(III), Cu(II), Zn(II) complexes were prepared. PPP4pT potent antiproliferative activity (IC

Язык: Английский

---

Multi-modal mechanisms of the metastasis suppressor, NDRG1: Inhibition of WNT/β-catenin signaling by stabilization of protein kinase Cα

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(7), С. 107417 - 107417

Опубликована: Май 28, 2024

Язык: Английский

---

NDRG1 acts as an oncogene in triple-negative breast cancer and its loss sensitizes cells to mitochondrial iron chelation

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Июнь 25, 2024

Multiple studies indicate that iron chelators enhance their anti-cancer properties by inducing NDRG1, a known tumor and metastasis suppressor. However, the exact role of NDRG1 remains controversial, as newer have shown can also act an oncogene. Our group recently introduced mitochondrially targeted deferoxamine (mitoDFO) deferasirox (mitoDFX) effective agents. In this study, we evaluated ability these modified to induce in breast cancer. We demonstrated both compounds specifically increase without other NDRG family members. documented effect is at least partially mediated GSK3α/β, leading phosphorylation Thr 346 lesser extent on Ser 330 . Loss increases cell death induced mitoDFX. Notably, MDA-MB-231 cells lacking exhibit reduced extracellular acidification rate grow slower than parental cells, while opposite true for ER+ MCF7 cells. Moreover, overexpression full-length N-terminally truncated isoform (59112) significantly sensitivity towards mitoDFX Furthermore, overexpressing exhibited accelerated formation, its isoforms showed impaired capacity form tumors. Thus, promotes growth highly aggressive triple-negative

Язык: Английский

---

Innovative N-Acridine Thiosemicarbazones and Their Zn(II) Complexes Transmetallate with Cu(II): Redox Activity and Suppression of Detrimental Oxy-Myoglobin Oxidation

Inorganic Chemistry, Год журнала: 2024, Номер 63(43), С. 20840 - 20858

Опубликована: Окт. 15, 2024

The coordination chemistry and electrochemistry of novel N-acridine thiosemicarbazones (NATs) were investigated along with their redox activity, antiproliferative efficacy, transmetalation, dissociation properties. ability NAT Fe(III) complexes to inhibit detrimental oxy-myoglobin (oxy-Mb) oxidation was also examined. NATs act as tridentate ligands a 2:1 L/Zn(II) complex crystal structure, revealing distorted octahedral geometry, where both bind Zn(II) in meridional conformation. exhibited fully reversible one-electron FeIII/II couples more positive potentials than the related clinically trialed thiosemicarbazone (e.g., [Fe(DpC)2]+) due electron-donating capacity acridine. Surprisingly, NAT-Zn(II) showed generally greater or similar activity ligands, Cu(II), complexes. This may be explained by (1) formation highly lipophilic that acts chaperone promote cellular uptake (2) dissociate undergo transmetalation redox-active Cu(II) complex. Of NAT-Fe(III) complexes, [Fe(AOBP)2]+ demonstrated significant (p < 0.0001) improvement preventing oxy-Mb thiosemicarbazone, DpC. article advances our understanding chemistry, electrochemistry, intriguing biological

Язык: Английский

---

Screening of BindingDB database ligands against EGFR, HER2, Estrogen, Progesterone and NF-κB receptors based on machine learning and molecular docking

Computers in Biology and Medicine, Год журнала: 2024, Номер 183, С. 109279 - 109279

Опубликована: Окт. 25, 2024

Язык: Английский

---