Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Remarkable Switch of Regioselectivity in Diels–Alder Reaction: Divergent Total Synthesis of Borreverine, Caulindoles, and Flinderoles

Switchable reaction patterns of dimerization of indole substituted butadienes via a Lewis acid and thermal activation are reported. While under acidic conditions dimerization occurred around the internal double bond of the dienophile, a complete switch of regioselectivity was observed under thermal conditions, where dimerization occurred around the terminal double bond of the dienophile. This switch of regioselectivity was further exploited for the divergent total synthesis of structurally diverse indole alkaloid natural products

Remarkable Switch of Regioselectivity in Diels–Alder Reaction: Divergent Total Synthesis of Borreverine, Caulindoles, and Flinderoles

Switchable reaction patterns of dimerization of indole substituted butadienes via a Lewis acid and thermal activation are reported. While under acidic conditions dimerization occurred around the internal double bond of the dienophile, a complete switch of regioselectivity was observed under thermal conditions, where dimerization occurred around the terminal double bond of the dienophile. This switch of regioselectivity was further exploited for the divergent total synthesis of structurally diverse indole alkaloid natural products

Biomimetic Total Syntheses of Borreverine and Flinderole Alkaloids

Dimeric indole alkaloids represent a structurally unique class of natural products having interesting biological activities. Recently, we reported the first total synthesis of flinderoles B and C, structurally unique and potent antimalarial natural products. Central to the design of the approach and by virtue of a one-pot, acid-catalyzed dimerization reaction, the route also provided total synthesis of the borreverine class of natural products. This full account details the progress of efforts that culminated in the protecting-group-free, six-step total synthesis of all of the flindersia alkaloids: dimethylisoborreverine, isoborreverine, flinderoles A–C, and their analogues. A biomimetic approach featuring a scalable and catalytic formal [3 + 2] cycloaddition and Diels–Alder reaction is outlined in detail. On the basis of the experimental observations, a detailed mechanism has been proposed for the dimerization of tertiary alcohol <b>28</b>

Remarkable Switch of Regioselectivity in Diels–Alder Reaction: Divergent Total Synthesis of Borreverine, Caulindoles, and Flinderoles

Switchable reaction patterns of dimerization of indole substituted butadienes via a Lewis acid and thermal activation are reported. While under acidic conditions dimerization occurred around the internal double bond of the dienophile, a complete switch of regioselectivity was observed under thermal conditions, where dimerization occurred around the terminal double bond of the dienophile. This switch of regioselectivity was further exploited for the divergent total synthesis of structurally diverse indole alkaloid natural products

The reversible inter-conversion of copper(ii) dimers bearing phenolate-based ligands in their monomers: theoretical and experimental viewpoints

Using the deprotonated forms of the tetradentate phenol amine ligands 2-(((1-methylbenzimidazol-2-yl)methyl)(pyridin-2-ylmethyl)amino)methyl)phenol (HL1) and 2-(((pyridin-2-ylmethyl)(quinolin-2-ylmethyl)amino)methyl)phenol (HL2), dinuclear copper(ii) complexes were synthesized. These ligands yielded two binuclear complexes with the composition [Cu-2(L-n)(2)](ClO4)(2) [n = 1, (1) and n = 2, (2)] and two mononuclear complexes with the compositions [Cu(HL1)(CH3CN)](ClO4)(2) (3) and [Cu(HL2) (CH3CN)(OClO3)](ClO4) (4), which have been characterized using X-ray crystallography, UV-Vis, and magnetic susceptibility measurements. The magnetic susceptibility studies of 1 and 2 indicate moderate antiferromagnetic coupling between the Cu-II ions through the mu-phenoxo bridges [J = -38(2) and -145(1) cm(-1), respectively], which is described by the Bleaney-Bowers dinuclear model. In contrast, 3 and 4 are devoid of any significant magnetic interactions between the mononuclear units. 3 and 4 show axial spectra typical of the d(9) (d(x2-y2) as the ground state) configuration. The dimer complexes 1 and 2 can be converted into the corresponding monomeric Cu(ii) complexes 3 and 4via adding two equivalents of an acid, such as perchloric acid (HClO4), to a CH3CN solution of the dimer. The dimeric core can be regenerated via adding an equivalent of a base, such as triethylamine (Et3N). Time-dependent density functional theory (TD-DFT) calculations using the M06 functional were performed in order to rationalize the electronic structures of the complexes and to shed light on the origin of the observed electronic transitions. Additionally, DFT/B3LYP calculations helped us to unambiguously state the sign and magnitude of the magnetic coupling constants along with an approximation of the spin density distribution

Structural and magnetic characterization of mixed-valence vanadium (IV/V) complex with {(VO)2(µ‒O)}3+ core: Theoretical and experimental insights

•In the current manuscript, we have reported mixed-valence vanadium (IV/V) and divanadium (V,V) complexes supported by tetradentate ligand. A reasonable good agreement between the J values obtained from experimental data and those obtained from Density Functional Theory (DFT) calculations at the B3LYP level of theory was achieved.•The rationalization of observed magnetic-exchange coupling constants was achieved, based on structural parameters (magnetostructural considerations). Theoretical calculations have been done to rationalized experimental electronic structure of complexes.•Although there are many reports on mixed-valence vanadium (IV,V) systems but this is the first report where we have reported the theoretical justifications for our experimental results of such complexes.•In current manuscript, we have attempted to highlights the importance of ligand design with varied denticity, donor atom type, rigidity/flexibility, bridging capability, and successful use of such ligands to synthesize several noteworthy transition metal complexes. Using deprotonated forms of tetradentate phenol amine ligands 2-(((1-methylbenzimidazol-2-yl)methyl)(pyridin-2-ylmethyl)amino)methyl)phenol (HL1), dinuclear vanadium(IV,V) complex of composition [(L1)2(VIVO)(µ-O)(VVO)](ClO4) (1) was synthesized and characterized by X–ray crystallography, UV–Vis, EPR and magnetic susceptibility measurements. Direct current (DC) variable-temperature magnetic susceptibility measurements on polycrystalline sample of 1 were carried out in the temperature range 1.8–300 K. Electron paramagnetic resonance and magnetic studies for 1 demonstrated the complete localization of the single 3d electron on one of vanadium ion and very weak antiferromagnetic interaction between the paramagnetic vanadium(IV) ions in the crystal lattice. The cyclic voltammogram observed with 1, revealed one oxidation process which is tentatively assigned to VIVVV/V2V. [(L1)2(VVO)2(µ-O)](ClO4)2 (2.2.5CH2Cl2) has been synthesized chemically from 1 and were thoroughly characterized by X–ray crystallography, UV–Vis, 51V NMR and IR measurements. [Display omitted

Improved Total Synthesis of Tubulysins and Design, Synthesis, and Biological Evaluation of New Tubulysins with Highly Potent Cytotoxicities against Cancer Cells as Potential Payloads for Antibody–Drug Conjugates

Improved, streamlined total syntheses of natural tubulysins such as V (<b>Tb45</b>) and U (<b>Tb46</b>) and pretubulysin D (<b>PTb-D43</b>), and their application to the synthesis of designed tubulysin analogues (<b>Tb44</b>, <b>PTb-D42</b>, <b>PTb-D47</b>–<b>PTb-D49</b>, and <b>Tb50</b>–<b>Tb120</b>), are described. Cytotoxicity evaluation of the synthesized compounds against certain cancer cell lines revealed a number of novel analogues with exceptional potencies [e.g., <b>Tb111</b>: IC₅₀ = 40 pM against MES SA (uterine sarcoma) cell line; IC₅₀ = 6 pM against HEK 293T (human embryonic kidney cancer) cell line; and IC₅₀ = 1.54 nM against MES SA DX (MES SA with marked multidrug resistance) cell line]. These studies led to a set of valuable structure–activity relationships that provide guidance to further molecular design, synthesis, and biological evaluation studies. The extremely potent cytotoxic compounds discovered in these investigations are highly desirable as potential payloads for antibody–drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies

Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins

A streamlined total synthesis of <i>N</i>¹⁴-desacetoxytubulysin H (<b>Tb1</b>) based on a C–H activation strategy and a short total synthesis of pretubulysin D (<b>PTb-D43</b>) are described. Applications of the developed synthetic strategies and technologies to the synthesis of a series of tubulysin analogues (<b>Tb2</b>–<b>Tb41</b> and <b>PTb-D42</b>) are also reported. Biological evaluation of the synthesized compounds against an array of cancer cells revealed a number of novel analogues (e.g., <b>Tb14</b>), some with exceptional potencies against certain cell lines [e.g., <b>Tb32</b> with IC₅₀ = 12 pM against MES SA (uterine sarcoma) cell line and 2 pM against HEK 293T (human embryonic kidney) cell line], and a set of valuable structure–activity relationships. The highly potent cytotoxic compounds discovered in this study are highly desirable as payloads for antibody–drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies