Combinatorial Synthesis to Identify a Potent, Necrosis-Inducing Rhenium Anticancer Agent

Abstract

Combinatorial synthesis can be applied for developing a library of compounds that can be rapidly screened for biological activity. Here, we report the application of microwave-assisted combinatorial chemistry for the synthesis of 80 rhenium­(I) tricarbonyl complexes bearing diimine ligands. This library was evaluated for anticancer activity in three different cancer cell lines, enabling the identification of three lead compounds with cancer cell growth-inhibitory activities of less than 10 μM. These three lead structures, Re-9B, Re-9C, and Re-9D, were synthesized independently and fully characterized by NMR spectroscopy, mass spectrometry, elemental analysis, and X-ray crystallography. The most potent of these three complexes, Re-9D, was further explored to understand its mechanism of action. Complex Re-9D is equally effective in both wild-type and cisplatin-resistant A2780 ovarian cancer cells, indicating that it circumvents cisplatin resistance. This compound was also shown to possess promising activity against ovarian cancer tumor spheroids. Additionally, flow cytometry showed that Re-9D does not induce cell cycle arrest or flipping of phosphatidylserine to the outer cell membrane. Analysis of the morphological changes of cancer cells treated with Re-9D revealed that this compound gives rise to rapid plasma membrane rupture. Collectively, these data suggest that Re-9D induces necrosis in cancer cells. To assess the in vivo biodistribution and stability of this compound, a radioactive 99mTc analogue of Re-9D, 99mTc-9D(H2O), was synthesized and administered to naı̈ve BALB/c mice. Results of these studies indicate that 99mTc-9D(H2O) exhibits high metabolic stability and a distinct biodistribution profile. This research demonstrates that combinatorial synthesis is an effective approach for the development of new rhenium anticancer agents with advantageous biological properties.

A Rhenium Isonitrile Complex Induces Unfolded Protein Response‐Mediated Apoptosis in Cancer Cells

“…[6][7][8][9][10][11] In this context,our group has been exploringthe anticancera ctivity of polypyridyl rhenium(I) tricarbonyl complexes. [12][13][14][15] Certain members of this class of compounds exhibit potent cytotoxic activity,w hich can be leveragedf or their use as anticancer agents. [16][17][18][19][20][21][22][23] Here, we describe our investigation of an ew rhenium(I) tricarbonyl complexb earing ac helating polypyridyl liganda nd an axial isonitrile ligand as ap otent anticancer agent.O ur efforts to understand the mechanismo f actiono ft his tricarbonyl rhenium isonitrile polypyridyl (TRIP) complex ( Figure 1) have revealed that it is an effective ER stress-inducing agent with significant antiproliferativeactivity.…”

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

“…The bioinorganic community has explored the use of coordination and organometallic compounds as inhibitors or as auxiliary groups to augment existing organic moieties, [17][18][19][20][21][22] and some of these metal-containing inhibitors having entered clinical trials, such as ferroquine. 23,24 A few uses of organometallic groups to augment existing organic inhibitors have produced spectacular results, including highly selective and active kinase inhibitors.…”

“…Complexes similar to those in Classes F and G with bidentate N,N donors have been investigated for their anticancer properties. 22,36 Classes H and I are carbene complexes; most reported biologically active metal-carbene complexes are prepared with Ag(I) and Au(I) and have shown anticancer and antimicrobial properties. that octahedral complexes in the library containing asymmetric bidentate ligands (Classes G and K) form enantiomeric mixtures due to different binding orientations of the bidentate ligand.…”

Highly Potent Rhenium(I) Tricarbonyl Complexes with Dual Anticancer and Anti-Angiogenic Activity Against Colorectal Carcinoma

“…The anticancer activity of fac-[Re(CO)3] + compounds has been tested on several different cancer cell lines. The majority of the studies were focused on antiproliferative effects on cervical, 30-33, 47, 51, 57-61 ovarian, 62,63 breast, 12,20,25,[64][65][66] and epithelial adenocarcinoma 24,49,67,68 cell lines showing IC50 values as low as e.g. 0.1 (HeLa), 30 1 (MCF-7), 15 0.75 (A549), 67 4 (NB69 and H4 cells) μM.…”