Syntheses, Structures, and Characterization of Metal Carbonyl Complexes as Photoactive CO Releasing Molecules and their Biological Utility Towards Eradication of Cancer
Carbon monoxide (CO) has recently been shown to elicit various salutary effects in mammalian physiology. This small molecule has shown to exert a multitude of actions, which includes, vasoregulation, inflammation reduction and anti-apoptotic actions in normal cells. Interestingly, in hyperproliferative cells, CO has shown to induce significant pro-apoptotic effects, which can be exploited therapeutically towards cancer eradication. However, the ability to deliver CO in a target-specific manner has been a tantalizingly challenging task. In order to tackle this issue, CO releasing pro-drugs have been developed in order to deliver CO in a more controlled fashion to cellular targets. However, a large number of such pro-drug molecules systemically release CO, a process that can hardly be controlled. We have employed metal carbonyl complexes (MCCs) to deliver CO upon light illumination, which are otherwise stable under dark conditions. The requirement of light of a particular wavelength to trigger CO photorelease from such MCCs is strictly dependent on complex design. The important goal is to develop an ideal MCC where CO release can be initiated upon illumination of lights of biocompatible wavelength range. The series of complexes in Chapter 2 bearing manganese(I), ruthenium(II), and rhenium(I) metal centers elucidates the design principles necessary to enable CO photorelease under certain ranges of light illumination. In such endeavor, the choice of organic ligand frame and co-ligand along with their geometrical placement are critical. The choice of metal also plays an important role in dictating the photo behavior of such complexes.
Chapter 3 utilizes the design principles established in chapter 2 and further explores the ligand design and steric features associated with organic ligand frame towards CO photorelease. These characteristics facilitated exceptionally rapid CO release under the control of visible light, thus affording a system ideal for application in certain therapeutic procedure that requires high local concentration of CO.
The subject matter of chapter 4 deals with developing a trackable CO delivery system without attenuation of the drug (CO) within the cellular matrices. The design principles for such trackable CO releasing MCC involved rigid ring ligand frames bound to manganese(I) metal center which resulted a “turn on” luminescence, and with a rhenium(I) metal center afforded a “two-tone” theranostic system upon CO delivery. In part 1, such Mn(I) carbonyl complex aided the tracking of CO release event within MDA-MB-231 cancer cells under the control of visible light, while in part 2 the internalization of a luminescent Re(I) complex pro-drug can be followed within biological matrices and a distinct second fluorescence signal is observed when the drug (CO) is released upon illumination.
The eventual obstacle towards developing a truly biocompatible CO releasing pro-drug (both sensitivity to visible light and aqueous solubility) is achieved in chapter 5. Two manganese carbonyl complexes incorporating rigid fluorescent α-diimine ligands are reported in this chapter. The inclusion of 1,3,5-triaza-7-phosphaadmantane (PTA) as ancillary ligand confers remarkable water solubility to such complexes. Both of these MCCs exhibit CO release upon low power visible light illumination. Taken together these features, it reasonable to assume that these CO releasing pro drugs have huge potential to find their place in clinic settings as phototherapeutics in near future.