(18-Crown-6)potassium(I) Trichlorido[28-acetyl-3-(tris-(hydroxylmethyl)amino-ethane)betulinic ester-κN]platinum(II): Synthesis and In Vitro Antitumor Activity

Abstract

Synthesis of platinum(II) conjugate with acetylated betulinic acid tris(hydroxymethyl) aminomethane ester (BATRIS) is presented (BATRISPt). HR-ESI-MS and multinuclear NMR spectroscopy, as well as elemental analysis were used for characterization of BATRISPt. Cytotoxicity (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), crystal violet (CV), and sulforhodamine B (SRB) assays) of BA, BATRIS, BATRISPt, and cisplatin were assessed on seven different tumor cell lines: melanoma B16, colon HCT116 and DLD-1, adenocarcinoma HeLa, breast MCF-7, and anaplastic thyroid tumor 8505C and SW1736; as well as normal MRC-5 fibroblasts. Furthermore, the effect of the mentioned compounds on the apoptosis (Annexin V/PI assay) and autophagy induction (acridine orange (AO) assay) as well as caspase 3, 8, and 9 activation were investigated on the selected B16 melanoma cell line. BATRISPt showed lower activity than BA, BATRIS, or cisplatin. All tested compounds triggered apoptosis in B16 cells. Induction of autophagy was observed in B16 cells exposed only to BATRIS. On the other hand, new conjugate activates caspases 8 and 9 in B16 cells with higher impact than BATRIS or cisplatin alone.Inorganics 2017, 5, 56 2 of 13 instance, how such compounds can be delivered, metabolized, and how and to which magnitude they may enter the tumor cells. On the other side, two components covalently linked to each other-double drug [13], presumably-may possess different behavior than single components alone.Even lower in activity than paclitaxel or doxorubicin [14,15], a cell-type-specific antitumor active compound betulinic acid (BA) has drawn more attention in the last few years and is still explored by many groups [16][17][18][19][20][21][22][23][24]. BA is a naturally occurring pentacyclic triterpenoid which is isolated from the bark of several species of plants (e.g., white birch). Betulinic acid and its derivatives present compounds with numerous biological activities-for instance, antioxidant, antiviral, antimicrobial, anti-inflammatory, antidiabetic, immunomodulatory, etc. [25,26]. However, investigations on betulinic acid in the last few years have been pointed toward the field of antitumor properties [27][28][29][30][31].We recently reported the synthesis and characterization of the new series of betulinic acid-cisplatin conjugates, which are both apoptosis inducing agents [32]. However, their cytotoxicity was found to be lower than parental drugs cisplatin and betulinic acid. Herein we report on the synthesis, characterization, and in vitro activity of acetylated betulinic acid derivative tris(hydroxymethyl)aminomethane (TRIS) ester conjugated with PtCl 3 -fragment.

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

“…The synthesis, characterization and in vitro antitumor activity of a platinum(II)‒acetylated BA tris(hydroxymethyl)aminomethane ester conjugate 206 were reported [95]. This complex showed lower activity than BA 1 , starting BA ester derivative 205 , and cisplatin.…”