Gold(III) Complexes in the Oncological Preclinical Arena: From Aminoderivatives to Peptidomimetics

Abstract

In the last decade, we have been developing some gold(III) derivatives showing interesting antitumor properties and reduced systemic and renal toxicity, compared to the clinically-established reference drug cisplatin. Starting from the rationale at the base of our investigations, this review has been divided into two sections, with respect to our patented first- (aminoderivatives) and secondgeneration (peptidomimetics) potential drugs. Every section describes the in vitro and in vivo anticancer activity of the compounds, chosen as models, towards different types of tumor. In particular, we summarize the results achieved so far, in particular taking into account the latest in-depth studies related to their activity, mechanism of action and toxicological profile. Taken together, our data could open up new prospects for further advanced preclinical pharmacological testing.

Anticancer Gold(III) Peptidomimetics: From Synthesis to in vitro and ex vivo Biological Evaluations

“…[11,15,53,69] For this class of complexes, DNA does not appear to be am ajor target, despite the great affinity for the isolatedD NA moleculea nd the capability to inhibit both RNA and DNA synthesis in ad ose-independent way,inc ontrast to what has been observed for cisplatin. [11,15,53,69] For this class of complexes, DNA does not appear to be am ajor target, despite the great affinity for the isolatedD NA moleculea nd the capability to inhibit both RNA and DNA synthesis in ad ose-independent way,inc ontrast to what has been observed for cisplatin.…”

“…Despite these restrictions, it is still administered to patients to treat testicularc ancera nd, in combination with other chemotherapeutics, some ovarian, small-cell lung, bladder,a nd breast tumors. [11] Moreover,n either cross-resistance nor the main drawbacks of cisplatin-based therapy were detected.I ndeed, in recenty ears, it was demonstrated that Au III -dithiocarbamato complexes exploit am echanism of action different from that of the clinically established platinum drugs. [7][8][9] In particular, research has focusedonthe synthesis of newc omplexesw ith better selectivity for cancerous cells and,consequently,with less side effects.…”

“…[6] The poor chemotherapeutic index of this widely clinically used drug gave rise to the development of second-and third-generation platinum-based derivatives and opened the frontiers to the design of new anticancer drugs based on alternative metals. [11,12] These promising results represented the starting point for the development of new second generation compounds, designedt oi mprove bioavailability,t umor selectivity, andc ellular uptake [13][14][15] rela-Five new Au III -peptidodithiocarbamatoc omplexeso ft he type [Au III Br 2 (dtc-AA 1 -AA 2 -OR] (in which AA 1 = N-methylglycine (Sar), l/d-Pro;A A 2 = l/d-Ala, a-aminoisobutyric acid (Aib);R = OtBu, triethylene glycol methyl ether), differing with regard to the amino acid sequence and/ort he chiral amino acid configuration, were designedt oe nhancet umor selectivity and bioavailability.T he gold(III)-based moiety was functionalized to exploit the targeting properties of the peptidomimetic ligand toward two peptidet ransporters (namely PEPT1 and PEPT2), which are upregulated in severalt umor cells. [10] In our researchg roup, new first generation Au III -dithiocarbamato compounds with the general formula [Au III X 2 (dtc)] (X = Cl, Br;d tc = various dithiocarbamates) were designed and prepared.…”

Transition Metal Intercalators as Anticancer Agents—Recent Advances

“…Nonetheless some recent examples of less common transition metal intercalators have emerged in the literature. For example, gold complexes have been relatively successful in medicinal chemistry [69,70,71], although most active anticancer complexes do not target DNA [72,73,74]. Recently reported macrocyclic gold(III) complexes that incorporated a quinoxaline moiety to promote DNA intercalation demonstrated cytotoxic activity [75].…”

Antiproliferative Activity of Gold(III) Complexes with Esters of Cyclohexyl-Functionalized Ethylenediamine-N,N’-Diacetate

“…Since gold(III) is isoelectronic to platinum(II) and both metals preferentially generate square planar complexes (d 8 system) a number of gold(III) complexes were synthesized and tested as an alternative to the anticancer drug cisplatin (22)(23)(24)(25)(26)(27). Due to the fact that the gold(III) has high reduction potential, a range of strategies has been applied in order to obtain gold(III) complexes with sufficient stability under physiologically relevant conditions.…”