Molybdenum Mediated Synthesis of Pentathiepins ‒ Potent Cytotoxic and Antimicrobial agents and Discovery of Novel Pd/PTABS Catalyst for The Synthesis of Pharmaceutically Relevant Drug Molecules via C‒N, C−O, and C−S Cross-coupling

In modern-day organic synthesis, transitional metal catalysis has become an essential tool-kit to access the biologically significant complex organic scaffolds. The activation profile of these sophisticated catalytic systems in cross-coupling chemistry and ring-closing processes has been well appreciated and frequently employed by the scientific community. The present thesis is describing the results of interdisciplinary research involving medicinal chemistry and transitional metal homogeneous catalysis. A molybdenum mediated process was employed to access 32 unprecedented heterocyclic fused poly sulfur ring containing pentathiepins in moderate to good yields as a part of medicinal chemistry. Biologically significant, such as quinoxaline, pyrazine, pyridine, nicotinamide, quinoline, imdazo-pyrazine, pyrrolo-pyrazine, purine, and pyridine sulfonamide scaffolds were functionalized with pentathiepin unit via multi-step organic synthesis. Essentially, the Sonogashira cross-coupling and(Et4N)2[MoO(S4)2] mediated ring-closing steps were commonly employed in all pentathiepin syntheses. The analytically pure samples were characterized by 1H, 13C, 19F-NMR, FTIR, ESI-MS, CHNS, and X-ray single-crystal diffraction analysis. Notably, all pentathiepins exhibited an ABX3 multiplet pattern between δ: 4.2-4.5 ppm with the integration of 2H for the ethoxy functional group's methylene protons substituted on the five-membered ring of pentathiepin, which was later considered as a fingerprint for pentathiepin formation. The mechanistic investigations via control experiments suggest that the tetra sulfur ring Mo(IV) precursor (Et4N)2[MoO(S4)2] is vital along with elemental sulfur for the pentathiepin formation, and the Mo(IV) complex regenerates in the reaction. Furthermore, For the first time, the GPx1 enzyme inhibitor properties of novel fused heterocyclic pentathiepins were established, where these probes exhibited 9-12 folds higher potency than mercaptosuccinic acid. Notably, <1 µM concentration of quinoxaline, pyrazine, and quinoline fused pentathiepins were potent enough to inhibit 50% of GPx1 enzyme activity. Additionally, cytotoxicity, antimicrobial and antifungal studies were conducted for all pentathiepins. In anticancer investigations, the IC50 concentrations for all pentathiepins were ranging between 0.22 to 4.7 µM. The second half of the thesis introduces a novel water-soluble Pd/PTABS as a potent catalyst for C-X (X = N, O, and S) cross-coupling chloroheteroarenes and halonucleosides. The novel, mild and efficient Pd/PTABS catalytic system was successfully employed at low catalytic loadings (1 mol%) for the amination (C−N), etherification (C−O), and thioetherification (C−S) of chloroheteroarenes at ambient to moderate temperatures. The Pd/PTABS catalyst is well-tolerating various heterocyclic scaffolds, and under the optimized catalytic conditions, various secondary amines, electron-rich or electron-poor phenols, thiophenols, and alkylthiols, were efficiently employed as nucleophilic coupling partners. Notably, the catalyst offered tremendous regio and chemoselectivity with excellent temperature control. Besides, novel sulfones and sulfoximines were prepared from the thioethers obtained via Pd/PTABS. The catalyst was employed efficiently for synthesizing biologically significant known drugs or drug candidates such as alogliptin (anti-diabetic agent), XRK 469 (antitumor agent), and Imuran-Azathioprine (immunosuppressive) in competitive yields. Preliminary DFT investigations were performed, and based on the DFT analysis, the electropositive character of the phosphorous atom in quaternary ammonium salts of PTABS supports the heteroatom directed C−Cl activation hypothesis.In der modernen organischen Synthese ist die Übergangsmetallkatalyse zu einem unverzichtbaren Werkzeug geworden, um Zugang zu den biologisch bedeutsamen komplexen organischen Gerüsten zu erhalten. Das Aktivierungsprofil dieser hoch entwickelten katalytischen Systeme in der Kreuzkupplungschemie und bei Ringschlussprozessen wurde von der wissenschaftlichen Gemeinschaft sehr geschätzt und häufig angewendet. Die vorliegende Arbeit beschreibt die Ergebnisse interdisziplinärer Forschung mit medizinischer Chemie und homogener Übergangsmetallkatalyse. Ein Molybdän-vermittelter Prozess wurde angewendet, um auf 32 beispiellose heterocyclische kondensierte Polyschwefelringe zuzugreifen, die Pentathiepine in mäßigen bis guten Ausbeuten als Teil der medizinischen Chemie enthielten. Biologisch signifikante Gerüste wie Chinoxalin, Pyrazin, Pyridin, Nicotinamid, Chinolin, Imdazopyrazin, Pyrrolopyrazin, Purin und Pyridinsulfonamid wurden über eine mehrstufige organische Synthese mit Pentathiepin-Einheiten funktionalisiert. Im Wesentlichen wurden die Sonogashira-Kreuzkupplung und (Et4N)2 [MoO(S4)2] - vermittelte Ringschlussschritte üblicherweise in allen Pentathiepin-Synthesen angewendet. Die analytisch reinen Proben wurden durch 1H-, 13C-, 19F-NMR-, FTIR-, ESI-MS-, CHNS- und Röntgen-Einkristallbeugungsanalyse charakterisiert. Bemerkenswerterweise zeigten alle Pentathiepine ein ABX3-Multiplettmuster zwischen δ: 4,2-4,5 ppm mit der Integration von 2H für die Methylenprotonen der Ethoxy-funktionellen Gruppe, die am fünfgliedrigen Pentathiepin-Ring substituiert waren, der später als Fingerabdruck für die Pentathiepin-Bildung angesehen wurde. Die mechanistischen Untersuchungen über Kontrollexperimente legen nahe, dass der Tetra-Schwefelring-Mo (IV) -Vorläufer (Et4N)2 [MoO(S4)2] zusammen mit elementarem Schwefel für die Pentathiepin-Bildung von entscheidender Bedeutung ist und sich der Mo (IV) -Komplex in der Reaktion regeneriert . Darüber hinaus wurden zum ersten Mal die GPx1-Enzyminhibitor-Eigenschaften neuer fusionierter heterocyclischer Pentathiepine ermittelt, wobei diese Sonden eine 9-12-fach höhere Wirksamkeit als Mercaptobernsteinsäure zeigten. Bemerkenswerterweise war eine Konzentration von <1 uM von Chinoxalin, Pyrazin und Chinolin-fusionierten Pentathiepinen stark genug, um 50% der GPx1-Enzymaktivität zu hemmen. Zusätzlich wurden für alle Pentathiepine Zytotoxizitäts-, antimikrobielle und antimykotische Studien durchgeführt. In Antikrebsuntersuchungen lagen die IC 50 -Konzentrationen für alle Pentathiepine zwischen 0,22 und 4,7 uM. In der zweiten Hälfte der Arbeit wird ein neues wasserlösliches Pd / PTABS als wirksamer Katalysator für die Kreuzkupplung von Chloroheteroarenen und Halonukleosiden mit C-X (X = N, O und S) vorgestellt. Das neue, milde und effiziente katalytische Pd / PTABS-System wurde erfolgreich bei niedrigen katalytischen Beladungen (1 Mol-%) zur Aminierung (C-N), Veretherung (C-O) und Thioetherifizierung (C-S) von Chloroheteroarenen bei Umgebungstemperatur eingesetzt zu moderaten Temperaturen. Der Pd / PTABS-Katalysator verträgt verschiedene heterocyclische Gerüste gut, und unter den optimierten katalytischen Bedingungen wurden verschiedene sekundäre Amine, elektronenreiche oder elektronenarme Phenole, Thiophenole und Alkylthiole effizient als nukleophile Kupplungspartner eingesetzt. Bemerkenswerterweise bot der Katalysator eine enorme Regio- und Chemoselektivität bei ausgezeichneter Temperaturkontrolle. Außerdem wurden neue Sulfone und Sulfoximine aus den über Pd / PTABS erhaltenen Thioethern hergestellt. Der Katalysator wurde effizient zur Synthese von biologisch signifikanten bekannten Arzneimitteln oder Arzneimittelkandidaten wie Alogliptin (Antidiabetikum), XRK 469 (Antitumormittel) und Imuran-Azathioprin (Immunsuppressivum) in wettbewerbsfähigen Ausbeuten eingesetzt. Vorläufige DFT-Untersuchungen wurden durchgeführt, und basierend auf der DFT-Analyse stützt der elektropositive Charakter des Phosphoratoms in quaternären Ammoniumsalzen von PTABS die heteroatomgerichtete C-Cl Aktivierungshypothese

7-((5-Bromo-1H-indol-3-yl)(4-methoxyphenyl)methyl)-1,3,5-triaza-7-phosphaadamantan-7-ium Tetrafluoroborate

The novel organic salt 7-((5-bromo-1H-indol-3-yl)(4-methoxyphenyl)methyl)1,3,5-triaza-7-phosphaadamantan-7-ium tetrafluoroborate was synthesized from a Lewis acid (LA) and Lewis-base (LB) reaction between 1,3,5-triaza-7-phosphaadmantane (LB) and 5-bromo-3-(4-methoxybenzylidene)-3-H-indol-1-ium tetrafluoroborate (LA). The obtained Lewis acid base adduct, being the title compound, was analyzed and validated by 1H, 13C, 31P, and 19F 1D-NMR-spectroscopy, ESI mass spectrometry, CHN-elemental analysis, and a single crystal X-ray diffraction investigation

Phosphine Ligands Based on the Ferrocenyl Platform: Advances in Catalytic Cross-Couplings

International audienceFerrocenyl skeletons tagged with a variety of donor atoms (metalloligands) have become popular in modern metal-catalyzed organic transformations, broadening the applications. Ferrocenylphosphines, such as 1′-bis(diphenylphosphino)ferrocene (dppf), have been widely used as metalloligands in academic and industrial research, motivating further investigation into novel ferrocenylphosphine ligands. The current review concentrated non-exhaustively on emblematic applications of different ferrocenylphosphine ligands in transition metal-catalyzed cross-coupling strategies. Initially, the stereochemical aspects of the ferrocenyl skeleton, nomenclature, and applications of chiral ferrocenyl phosphines in asymmetric synthesis are evoked. We simply classified ferrocenyl phosphine ligands, eventually further functionalized at cyclopentadienyl (Cp) ring, into three types based on the number of phosphine donors on the ferrocenyl backbone: monophosphine, bisphosphine, and polyphosphine ferrocenyl ligands. Furthermore, the use of hybrid monophosphinoferrocene type scaffolds (P, N)–, (P, O)–, (P, S–), (P, NHC)–, and (P, X)– (X is polar/hydrophilic like guanidium) in cross-coupling is evoked. The latest advances in the chemistry of symmetric achiral di- and polyphosphine ferrocene-based ligands related to metal-catalyzed bond-forming reactions (C–C, C–N, and C–O bonds) are discussed, with a special emphasis on consolidating all important work in this area. A cumulative table is provided in the end, with a focus on compiling significant work in this field. The general structure and electronic features and effects of ferrocenylphosphine ligands on the selectivity and activity in catalysis is also briefly evoked. The literature cut-off date was in general ending of 2020

Comprehensive evaluation of biological effects of pentathiepins on various human cancer cell lines and insights into their mode of action

Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future