Synthetic Strategies for the Preparation of Gold‐based Anticancer Agents

Abstract

Gold (Au) complexes attained an exceptional reach as new metal‐based anticancer agents in recent years. The FDA‐approved Au I complex auranofin [(2,3,4,6‐tetra‐ O ‐acetyl‐1‐thio‐β‐ d ‐glucopyranose (triethylphosphoranylidene)gold(I)] displays efficacious chemotherapeutic potential in phase I and II clinical trials for both liquid and solid tumors. Ignited by the success of auranofin as an anticancer agent, new designs and synthetic processes toward Au I and Au III complexes for unique biomedical applications are actively ongoing. In the past few years, Au III complexes have become attractive as premised on promising antitumor preclinical studies despite bottlenecks associated with stability and biological target identification. Advancement of gold complexes to the clinic will require agents with improved anticancer potency, unambiguous biological target, pharmacokinetic profile, and optimal stability. Thus, ligand tuning and innovative synthetic chemistry coupled with rigorous biological characterization are crucial. In this article, an overview of known synthetic strategies for the synthesis of gold anticancer complexes is presented. Primary focus on the synthesis of Au I and Au III complexes along with anticancer outcomes is outlined. This article presents medicinal inorganic chemists with an armory of synthetic tools and purification protocols to readily access highly potent gold anticancer agents.

Next Generation Gold Drugs and Probes: Chemistry and Biomedical Applications

“…We must mention that detailed synthetic methodologies for the preparation of gold complexes are out of the scope of this Review. However, readers are encouraged to visit the articles cited at the end of the Review to peruse creative synthetic strategies outlined as well as a recently reviewed strategies to preparing gold anticancer complexes . Despite the drawbacks, new possibilities have arisen within the past decade to developing next generation gold agents beyond auranofin, the “gold standard.” Progressively, evidence of (i) the importance of gold in medicine, (ii) the success of gold in clinical trials (14 to date), (iii) the determination and creativity of scientists, and (iv) state-of-the-art technologies will propel next generation gold agents into clinical use.…”

Serum-Stable Gold(III) Bisphosphine Complex Induces Mild Mitochondrial Uncoupling and In Vivo Antitumor Potency in Triple Negative Breast Cancer

“…Structural modifications to gold-containing scaffolds result in complexes manifested by changes in oxidation states, geometry, and different chelating ligands to stabilize the gold center. − Notable work includes the development of mitochondrial targeting Au­(I)-NHCs and Au­(I)-(DPPE) 2 Cl that showed high cytotoxicity against cancer cells in vitro and in vivo but failed in preclinical toxicity studies. , Furthermore, Au­(III)-dithiocarbamate complexes trigger proteosome inhibition and potent in vivo effects . Gold porphyrin is another class of Au­(III) complexes with an excellent cytotoxic profile in a panel of cancer cells and inhibited tumor growth in mice with multiple mechanisms of action depending on the tetranitrogenic porphyrin ligand used. − To resolve the existing problem of Au­(III) complex instability, we and others have used cyclometalation as a strategy to improve compound stability in solution. − Recent speciation studies using chiral Au­(III) complexes with glutathione deepened our understanding into Au­(III) stability; however, enhanced complex stability will facilitate clinical translation of gold therapeutic agents .…”

A Conformationally Restricted Gold(III) Complex Elicits Antiproliferative Activity in Cancer Cells

“…24,31−34 There is extensive literature describing the utility of organogold Au(III) complexes in catalysis, 35−39 materials science, 40−43 sensors, 44−46 and anticancer activity. 47−56 Although organometallic Au(III) complexes bearing N^N bidentate ligands with sp 2 -hybridized nitrogen (N) have recently been reported, 57−60 bidentate ligands bearing sp 3 hybridized primary or secondary amines are underexplored, yet they hold tremendous potential for accessing stable but distinct scaffolds. 24 This has implications for their reactivity and consequent applications.…”

“…The resurgence of gold (Au) chemistry over the past two decades has contributed to the development of synthetic methods, − catalytic transformations, , materials for electronics, , reagents for bioorthogonal reactions, protein modifications, , and therapeutic agents. − In the context of drug discovery, great impetus is derived from auranofin, a Food and Drug Administration (FDA)-approved drug for treating rheumatoid arthritis . Although Au­(III) complexes are highly valent and present opportunities for ligand tuning due to having more coordination sites than conventional linear Au­(I), the instability of Au­(III) has been its Achilles’ heel.…”