New Apoptosis Inducers Containing Anti-inflammatory Drugs and Pnictogen Derivatives: A New Strategy in the Development of Mitochondrial Targeting Chemotherapeutics

Abstract

{[Ag8(Mef)8(μ2-S,O-DMSO)2(μ2-O-DMSO)2(O-DMSO)8]·2(H2O)} (1), [Ag(Mef)(tpP)2] (2), [Ag(Mef)(tpAs)3] (3), and {2 [Ag(Mef)(tpSb)3] (DMSO)} (4) were obtained by the conjugation of mefenamic acid (MefH), a nonsteroidal anti-inflammatory drug (NSAID), with a mitochondriotropic derivative of pnictogen tpE (tp = triphenyl group; E = P, As, and Sb) through silver(I). Their hydrophilicity was adjusted by their dispersion into sodium lauryl sulfate (SLS), forming SLS@1–4. 1–4 and SLS@1–4 were characterized by their spectral data and X-ray crystallography. They inhibit the proliferation of human breast adenocarcinoma cells MCF-7 (hormone-dependent (HD)) and MDA-MB-231 (hormone-independent (HI)). X-ray fluorescence reveals the Ag cellular uptake. The in vitro and in vivo nongenotoxicity was confirmed with micronucleus (MN), Artemia salina, and Allium cepa assays. Their mechanism of action was studied by cell morphology, DNA fragmentation, acridine orange/ethidium bromide (AO/EB) staining, cell cycle arrest, mitochondrial membrane permeabilization tests, DNA binding affinity, and LOX inhibitory activity and was rationalized by regression analysis.

Conjugation of an anti-metabolite nucleobase analogue with a mitochondriotropic agent via palladium(II) against breast cancer cells

“…The untreated cells are elongated, adherent, and showed cellular crowding. The treated cells, on the other hand, show cell shrinkage, detachment, and rounding up, the cell contact is lost, and they form islets of more rounded cells (Banti et al, 2016;Chrysouli et al, 2018;Stathopoulou et al, 2021;Kapetana et al, 2022;Banti et al, 2023). The observational experiment displayed that the MCF-7 cells exposed to 1 showed more destructive changes in their morphology compared to untreated cells.…”

“…DNA Binding Studies: DNA has been extensively studied as a potential pharmacological target of metalotherapeutics. The DNA binding affinity towards 1 was investigated (Banti et al, 2015;Banti et al, 2016;Chrysouli et al, 2018;Stathopoulou et al, 2021;Kapetana et al, 2022;Banti et al, 2023). The DNA-1 complex formation is studied here by (i) viscosity measurements, (ii) absorption titration, (iii) fluorescence spectroscopy and (iv) by the DNA Thermal Denaturation (Banti et al, 2015;Banti et al, 2016;Chrysouli et al, 2018;Stathopoulou et al, 2021;Kapetana et al, 2022;Banti et al, 2023).…”

“…This combination of disparate agents offers the potential for synergistic effects. One of the prominent domains fostering innovative synergistic therapeutic modalities is the Conjugation of Metals with specific classes of Drugs (CoMeD) (Banti et al, 2016;Banti et al, 2023). Over the past two decades, mitochondria have emerged as a primary pharmacological target in the development of new cancer chemotherapeutics.…”

“…The accumulation of positively charged compounds within the mitochondrial matrix is facilitated by the negative inner membrane potential (Zhu et al, 2019). Mitochondriotropic lipophilic cations, like trialkyl derivatives of pnictogens (Ar 3 E, where E= P, As, Sb), are specifically targeted to mitochondria, resulting in the disruption of mitochondrial membrane permeability (Banti et al, 2016;Banti et al, 2023). Furthermore, the anti-metabolite, exemplified by the nucleobase analogue 2thiouracil (TUC) and its derivatives are utilized in crafting and advancing targeted anticancer metallodrugs.…”

“…During our research endeavors aimed at creating novel metalbased therapeutics for chemotherapy through the Conjugation of Metals with Drugs (CoMeD) (Banti et al, 2015;Banti et al, 2016;Chrysouli et al, 2018;Stathopoulou et al, 2021;Kapetana et al, 2022;Banti et al, 2023), the palladium(II) metallodrug of the formula [PdCl(TOTP)(MTUC)] (TOTP= Tri-o-Tolyl-Phosphine and MTUC= 6-methyl-thiouracil (Scheme 1)) was synthesized and characterized. The synergy, by the conjugate of the mitochondriotropic agent TOTP and the uracil analogue MTU, via Pd(II) ions, might lead to a better chemotherapeutic.…”