Iron Catalysis of C(sp3)-H Azidation Using a Heteroarene Radical Cation Strategy.

The FeIII(phen)3 catalysis of the benzylic C(sp3)-H azidation of indoles has been investigated. The Fe(III) complex can selectively oxidize indoles to form arene radical cations, which are transformed into benzylic C(sp3) radical intermediates. This strategy exhibits a difference in reactivity between N-heteroarenes and benzene, which is difficult to achieve via direct hydrogen abstraction approaches. Various biorelevant azide precursors were constructed, highlighting the utility of this mild first-row transition-metal catalyst system.

Design, Synthesis and Evaluation of Novel (E)-N'-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as Antitumor Agents.

BACKGROUND: Herein, we have designed and synthesized a series of the novel (E)-N'-((1-(4-chlorobenzyl)- 1H-indol-3-yl)methylene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5) as potent small molecules activating procaspase- 3. The compounds were designed by the amalgamation of structural features of PAC-1 (the first procaspase-3 activator) and oncrasin-1, one potential anticancer agent. METHODS: The target acetohydrazides (5a-m) were prepared via the Niementowski condensation of anthranilic acid (1a) or 5-substituted-2-aminobenzoic acid (1b-m) and formamide. The compound libraries were evaluated for their cytotoxicity, caspase-3 activation, cell cycle analysis, and apoptosis. In addition, computational chemistry is also performed. RESULTS: A biological evaluation revealed that all thirteen compounds designed and synthesized showed strong cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer) with eight compounds (5a, 5c-i, 5k), which were clearly more potent than both PAC-1 and oncrasin-1. In this series, four compounds, including 5c, 5e, 5f, and 5h, were the most potent members with approximately 4- to 5-fold stronger than the reference compounds PAC-1 and oncrasin-1 in terms of IC50. In comparison to 5-FU, these compounds were even 18- to 29-fold more potent in terms of cytotoxicity in three human cell lines tested. In the caspase activation assay, the caspase activity was activated to 285% by compound 5e compared to PAC-1, the first procaspase activating compound, which was used as a control. Our docking simulation revealed that compound 5e was a potent allosteric inhibitor of procaspase-3 through chelation of inhibitory zinc ion. Physicochemical and ADMET calculations for 5e provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent. CONCLUSION: Compound 5e has emerged as a potential hit for further design and development of caspases activators and anticancer agents.

Design, synthesis, and evaluation of novel N'-substituted-1-(4-chlorobenzyl)-1H-indol-3-carbohydrazides as antitumor agents.

In continuity of our search for novel anticancer agents acting as procaspase activators, we have designed and synthesised two series of (E)-N'-benzylidene-carbohydrazides (4a-m) and (Z)-N'-(2-oxoindolin-3-ylidene)carbohydrazides (5a-g) incorporating 1-(4-chlorobenzyl)-1H-indole core. Bioevaluation showed that the compounds, especially compounds in series 4a-m, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Within series 4a-m, compounds with 2-OH substituent (4g-i) exhibited very strong cytotoxicity in three human cancer cell lines assayed with IC50 values in the range of 0.56-0.83 µM. In particular, two compounds 4d and 4f bearing 4-Cl and 4-NO2 substituents, respectively, were the most potent in term of cytotoxicity with IC50 values of 0.011-0.001 µM. In caspase activation assay, compounds 4b and 4f were found to activate caspase activity by 314.3 and 270.7% relative to PAC-1. This investigation has demonstrated the potential of these simple acetohydrazides, especially compounds 4b, 4d, and 4f, as anticancer agents.

Redox-Selective Iron Catalysis for α-Amino C-H Bond Functionalization via Aerobic Oxidation.

Single-electron oxidation and α-deprotonation of tertiary anilines using Fe(phen)3(PF6)3 afford α-aminoalkyl radicals, which can be coupled with electrophilic partners to afford various tetrahydroquinolines. Mechanistically, the Fe(phen)n2+/3+ catalytic cycle is maintained by O2 or a TBHP oxidant, and the presence of the oxygen bound iron complex, Fe(III)-OO(H), was elucidated by electron paramagnetic resonance and electrospray ionization mass spectrometry. This redox-selective nonheme iron catalyst behaves similarly to bioinspired heme iron catalysts.

(E)-N'-Arylidene-2-(4-oxoquinazolin-4(3H)-yl) acetohydrazides: Synthesis and evaluation of antitumor cytotoxicity and caspase activation activity.

In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-ones (5, 6, 7). Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU. Analysis of structure-activity relationships showed that the introduction of different substituents at C-6 position on the quinazolin-4(3H)-4-one moiety, such as 6-chloro or 6-methoxy potentially increased the cytotoxicity of the compounds. In term of caspase activation activity, several compounds were found to exhibit potent effects, (e.g. compounds 7 b, 5n, and 5l). Especially, compound 7 b activated caspases activity by almost 200% in comparison to that of PAC-1. Further docking simulation also revealed that this compound potentially is a potent allosteric inhibitor of procaspase-3.

Cd226-/- natural killer cells fail to establish stable contacts with cancer cells and show impaired control of tumor metastasis in vivo.

CD226 is an activating receptor expressed on natural killer (NK) cells, CD8+ T cells, and other immune cells. Upon binding to its ligands expressed on target cells, CD226 activates intracellular signaling that triggers cytokine production and degranulation in NK cells. However, the role of CD226 in contact dynamics between NK and cancer cells has remained unclear. Our time-lapse images showed that individual wild-type CD226+ NK cells contacted B16F10 melanoma cells for 23.7 min, but Cd226-/- NK cells only for 12.8 min, although both NK cell subsets showed equal contact frequency over 4 h. On the surface of B16F10 cells, CD226+ cells stayed at the same site with oscillating movement (named stable contact), while Cd226-/- NK cells moved around at a velocity of 4 µm/min (named unstable contact). Consequently, Cd226-/- NK cells did not kill B16F10 cells in vitro and did not inhibit their metastasis into the lung in vivo. Taken together, our data demonstrate that CD226 enables prolonged stable interaction between NK and cancer cells, which is needed for efficient killing of cancer cells.