The Power of Kinetic Inertness in Improving Platinum Anticancer Therapy by Circumventing Resistance and Ameliorating Nephrotoxicity

Even in the modern era of precision medicine and immunotherapy, chemotherapy with platinum (Pt) drugs remains among the most commonly prescribed medications against a variety of cancers. Unfortunately, the broad applicability of these blockbuster Pt drugs is severely limited by intrinsic and/or acquired resistance, and high systemic toxicity. Considering the strong interconnection between kinetic lability and undesired shortcomings of clinical Pt drugs, we rationally designed kinetically inert organometallic Pt based anticancer agents with a novel mechanism of action. Using a combination of in vitro and in vivo assays, we demonstrated that the development of a remarkably efficacious but kinetically inert Pt anticancer agent is feasible. Along with exerting promising antitumor efficacy in Pt-sensitive as well as Pt-resistant tumors in vivo, our best candidate has the ability to mitigate the nephrotoxicity issue associated with cisplatin. In addition to demonstrating, for the first time, the power of kinetic inertness in improving the therapeutic benefits of Pt based anticancer therapy, we describe the detailed mechanism of action of our best kinetically inert antitumor agent. This study will certainly pave the way for designing the next generation of anticancer drugs for effective treatment of various cancers.     

Energy-efficient syngas production through catalytic oxy-methane reforming reactions

The considerable recent interest in the conversion of stranded methane into transportable liquids as well as fuel cell technology has provided a renewed impetus to the development of efficient processes for the generation of syngas. The production of syngas (CO/H2), a very versatile intermediate, can be the most expensive step in the conversion of methane to value-added liquid fuels. The catalytic oxy reforming of methane, which is an energy-efficient process that can produce syngas at extremely high space-time yields, is discussed in this Review. As long-term catalyst performance is crucial for the wide-scale commercialization of this process, catalyst-related studies are abundant. Correspondingly, herein, emphasis is placed on discussing the different issues related to the development of catalysts for oxy reforming. Important aspects of related processes such as catalytic oxy-steam, oxy-CO2, and oxy-steam-CO2 processes will also be discussed.     

Total synthesis of clavosolide A

For the total synthesis of (−)-clavosolide A described herein, a Schmidt glycosidation reaction was used to attach the sugar moiety at an early stage in the synthesis to the 4-hydroxy group of the substituted tetrahydropyran unit of the molecule, which itself was built following a Ti(III)-mediated method developed by us earlier, and at the end, it was the Yamaguchi reaction that was successfully employed for the cyclodimerization of the two halves of the molecule leading to its total synthesis.     

Total synthesis of hyptolide

The total synthesis of hyptolide, a naturally occurring α,β-unsaturated six-membered δ-lactone substituted with a polyoxygenated chain, is described. Sharpless kinetic resolution and opening of two different epoxy alcohols under two different conditions—Swern oxidation conditions and a radical reaction using Cp₂TiCl—fixed the stereocenters at C-9, C-11, and C-12, respectively. Brown’s asymmetric allylation reaction installed the remaining stereocenter at C-6. A RCM protocol was used for construction of the α,β-unsaturated six-membered δ-lactone moiety of the molecule.     

Re-visiting of 5-[(E)-2-(aryl)-1-diazenyl]-quinolin-8-ol with tweaking of Sn-Ph groups: Synthesis, spectroscopic characterization and X-ray crystallography

Reactions of sodium 5-[(E)-2-(aryl)-1-diazenyl]quinolin-8-olates (LH, where the aryl group is an R-substituted phenyl ring such that for L¹H: R = H; L²H: R = 2′-CH₃; L³H: R = 3′-CH₃; L⁴H: R = 4′-CH₃; L⁵H: R = 4′-OCH₃ and L⁶H: R = 4′-OC₂H₅) with Ph₃SnCl in a 1:1 molar ratio yielded complexes of composition Ph₃SnL. The complexes have been characterized by ¹H, ¹³C, ¹¹⁹Sn NMR, IR and ^119mSn Mössbauer spectroscopic techniques in combination with elemental analyses. The crystal structures of Ph₃SnL¹ · 0.5C₆H₆ (1), Ph₃SnL² (2), Ph₃SnL⁵ · C₆H₆ (5) and Ph₃SnL⁶ · 0.5C₆H₆ (6) were determined. The results of the X-ray studies indicated that the benzene solvated compounds 1, 5 and 6 are distorted square pyramid, with one of the phenyl C atoms in the apex while the ligand arrangement around central Sn atom in 2 is distorted trigonal-bipyramidal, with a phenyl C and the oxinato N atoms in axial positions.     

Determination of nebivolol and valsartan in a fixed-dose combination by liquid chromatography

An accurate and reproducible liquid chromatographic assay method was developed and validated for the determination of nebivolol and valsartan in a capsule formulation. Buffer-acetonitrile (55 + 45, v/v) was used for reversed-phase liquid chromatography to determine the contents of nebivolol and valsartan in the combination-capsule dosage form. The method was validated by determining parameters such as specificity, linearity, limits of detection and quantitation, precision, accuracy, and robustness. The method was found to be specific against placebo interference. Linearity was evaluated over the concentration ranges of 2-8 micro/mL for nebivolol and 32-128 microg/mL for valsartan (the correlation coefficient was 0.9999 for both nebivolol and valsartan). Both the intraday and interday precision values of the system and the method were determined. The accuracy of the method ranged from 100.66 to 102.58% for nebivolol and from 101.17 to 101.85% for valsartan. The proposed method was found to be robust when slight but deliberate changes were made in the analytical conditions. The developed method was found suitable for the assay determination of nebivolol and valsartan in a capsule formulation.     

Displacement of the indolyl sulfide linkage in the synthesis of 3-substituted indoles

The indolyl sulfide compounds ( 5,6,7,8 ) gave 3-3′-diindole methane derivatives by a double decomposition-displacement reaction. These same compounds when reacted with alkoxides yielded 3-alkoxy-methylindole derivatives ( 9-14 ).     

Color test for the detection of resin-bound aldehyde in solid-phase combinatorial synthesis

We report the development of a sensitive and specific color test for the detection of the presence of resin-bound aldehyde groups using 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (Purpald). Aldehyde resin turns dark-brown to purple after a 5 min reaction followed by a 10 min air oxidation period. Resins that possess other functional groups (i.e., ketone, ester, amide, alcohol, and carboxylic acid) do not change color under the same conditions. The detection limit is 20 micromol/g for polystyrene-based aldehyde resins.     

Hydroxamic acid dinuclear complexes of molybdenum(V) and molybdenum(III)

Summary Molybdenum(V) and molybdenum(III) complexes [Mo₂O₃L₄] and [Mo₂L₆] derived from hydroxamic acids (HL) were prepared and identified by Raman, i.r., e.s.r., electronic spectra and analytical data. The low magnetic moments of the dinuclear complexes are due to in part to intramolecular interactions. Electronic spectra and vibrational studies indicate the presence of a Mo₂O₃ core in the molybdenum(V) complexes. The relative intensities of the, main and satellite peaks in e.s.r. spectra indicate the dinulcear nature of molybdenum(III) hydroxamates.