Design, synthesis and evaluation of structurally diverse ortho-acylphenol-diindolylmethane hybrids as anticancer agents

A highly efficient synthesis of structurally diverse ortho-acylphenol–diindolylmethane hybrids 3 using carboxylic acid-activated chromones as versatile synthetic building blocks is reported here for the first time, through 1,4-nucleophilic addition and followed by a decarboxylation and pyrone ring opening reaction process.

Ring-Opening of Epoxides by Pendant Silanols

We present a new ring-opening reaction of epoxides by pendant silanols, catalyzed by either Ph3C+BF4– or BINOL-phosphoric acid. In all cases examined, the reaction is perfectly regioselective and diastereoselective. Silanol epoxides derived from trans-allylic alcohols, cis-allylic alcohols, trans-homoallylic alcohols, and cis-homoallylic alcohols were all compatible and gave products from either endo- or exo-ring opening. With silanol epoxides derived from 4-alkenyl silanols, an unusual rearrangement to tetrahydrofuran products was observed, which is likely the result of tandem nucleophilic attacks. The utility of this methodology was demonstrated in a short preparation of protected D-arabitol.

pH-Dependent Selective Colorimetric Detection of Proline and Hydroxyproline with Meldrum’s Acid-Furfural Conjugate

Activated 2-furfural gives intense color formation when reacted with amines, due to a ring opening reaction cascade that furnishes a conjugated molecular system. Unique colorimetric characteristic of this reaction makes it an interesting candidate for developing chemosensors operating in visible range. Among many activated 2-furfural derivatives, Meldrum’s acid furfural conjugate (MAFC) recently gained significant interest as colorimetric chemosensor. MAFC has been explored as selective chemosensor for detecting amines in solution, secondary amines on polymer surfaces and even nitrogen rich amino acids (AA) in aqueous solution. In this work, the pH dependency of MAFC-AA reaction is explored. It was found that proline gives an exceptionally fast colored reaction at pH 11, whereas at other pHs, no naked eye color product formation was observed. The reaction sequence including ring opening reaction upon nucleophilic addition of cyclic amine of proline resulting in a conjugated triene was confirmed by NMR titrations. The highly pH dependent reaction can e.g., potentially be used to detect proline presence in biological samples. An even more intense color formation takes place in the reaction of natural proline derivative 4-hydroxyproline. The detection limit of proline and 4-hydroxyproline with MAFC solution was found to be 11 µM and 6 µM respectively.

Identifying the Mechanism of Action of Bioactive 1,2-Cyclopropyl Carbohydrates

<p>Cyclopropanes and carbohydrates have long been used in the field of drug development. Previous work has shown that 1,2-cyclopropyl carbohydrates display bioactivity in both HeLa cancer cell lines¹ and in yeast² with a tentatively proposed mechanism of inhibition occurring through an enzymatic cyclopropane ring opening reaction and subsequent formation of a covalent bond with a target enzyme.² A small library of 1,2-cyclopropyl carbohydrate derivatives were synthesised based on known pharmacophores to examine further the potential mechanism of inhibition of such compounds and confirm the occurrence of enzyme-catalysed cyclopropane ring-opening reactions. Initial synthetic efforts were focused on the synthesis of the 1,2-dichlorocyclopropyl carbohydrate 23, which, through the optimisation of an essential C-6 detritylation reaction, was achieved in moderate yields of 32% over 7 steps. Following this, the ethoxycarbonyl substituted 1,2-cyclopropyl carbohydrate 54 was synthesised over 7 steps in a 22% yield through a rhodium acetate-catalysed addition of ethyl diazoacetate (49) to the glucal substrate 40. It was envisioned that if enzymatic cyclopropane ring-opening was occurring to form a C-7 carbanion, this would in turn be stabilised through the potential enolate formation of 54. Use of N,N-ditosylhydrazine in the synthesis of propargyl diazoacetate (58) followed by a rhodium acetate-catalysed cyclopropanation of 58 with substrate 40 resulted in the successful synthesis of 61 over 7 steps in a total yield of 9%. The incorporation of the propargyl substituent in 61 was introduced as a molecular probe in an attempt to isolate the target protein through an affinity purification procedure. The bioactivity of the propargyl derivative 61 was consistent with the synthesised compounds 23 and 54. It was proposed that these compounds undergo an enzymatic cyclopropane ring opening reaction accompanied with a clear diastereoselective preference for the α-stereoisomer of the cyclopropane ring, consistent with a target-based activation of the compounds. Chemical genetic analysis of the resulting bioactive compounds was undertaken using a deletion mutant array of Saccharomyces cerevisiae to elucidate a potential mechanism of action. Analysis of the results showed that, of the 4800 homozygous deletion strains tested in the high-throughput screens, a total of 122 strains were found following validation to sensitise and 68 to give resistance against 23 and 54. These sensitive and resistant mutants were subjected to a validation assay. Following validation, genes whose deletion led to sensitivity or resistance were then subjected to gene ontology term enrichment analysis which showed enrichment in the cytosolic ribosome, SNARE complex and SNAP receptor activity for resistant strains and enrichment in endoplasmic reticulum and endomembrane systems was found for the sensitive strain. Genes whose deletion sensitised to both compounds showed strong enrichment in cellular protein localisation, intra-golgi vesicale-mediated transport and the endomembrane system. Target identification and isolation were attempted through an affinity purification procedure using compound 61 and an azide-modified agarose resin. However, this was without success, either through inaccessibility of the alkyne of the target probe or because the target resides in the membrane-associated fraction which was discarded prior to treatment with the probe. This study suggests that the 1,2-cyclopropyl carbohydrates synthesised function through a cyclopropane ring-opening reaction, assisted by an enzymatic nucleophile. Chemical genetic analysis showed that the target of these compounds is involved in protein transport and protein localisation most likely relating to the vesicle tethering. Although many aspects of this work still need further investigation, either through the synthesis of new 1,2-cyclopropyl carbohydrates to increase bioactivity and better understand the enzymatic target, or through further biological procedures to better understand the mechanism of action, the use of 1,2-cyclopropyl carbohydrates as a potential pharmaceuticals or probes of protein trafficking shows much promise.</p>

Platinum Complexes of Bicyclopropylidene and Related Ligands

<p>The coordination chemistry of the cyclopropyl-substituted alkenes, bicyclopropylidene (BCP) and methylenecyclopropane (MCP), with platinum was explored. A range of complexes with ŋ²-alkene ligands were synthesised by the displacement of a ligand, typically ethene, from a precursor complex. These complexes are [Pt(L)(P—P)] (L = BCP, MCP; P—P = Ph₂P(CH₂)₃PPh₂, Cy₂P(CH₂)₂PCy₂, ᵗBu₂P(CH₂)₂PᵗBu₂, ᵗBu₂PCH₂(o-C₆H₄)₂PᵗBu₂), [Pt(L)(P—S)] (L = BCP, MCP; P—S = ᵗBu₂PCH₂(o-₆H4)CH₂SᵗBu), [Pt(C₂H4)(L)(PR₃)] (L = BCP, MCP; PR₃ = PPh₃, PCy₃), [Pt(MCP)₂(PR₃)] (PR₃ = PPh₃, PCy₃) and [PtCl₂(L)(L′)] (L = BCP, MCP; L′ = Py, DMSO). These were the first examples of platinum complexes with ŋ²-BCP ligands, and the first bis-MCP Pt complexes. BCP underwent ring-opening reactions with both Pt(0) and Pt(II) complexes to form the 1,3-diene allylidenecyclopropane (ACP). The first transition metal complexes of ACP [Pt(ACP)(P—P)] (P—P = Ph₂P(CH₂)₃PPh₂, Cy₂P(CH₂)₂PCy₂, ᵗBu₂P(CH₂)₂PᵗBu₂) were synthesised. Some of these complexes rearranged to form ŋ²:σ²-metallacyclopentene complexes, the first instances of the formation of ŋ²:σ²-metallacyclopentene complexes from ŋ²:π-diene complexes. With MCP, the ring-opening reaction only occurred with [₂(COD)], as a result of the anti-Markovnikov addition of Pt–H, generated by the β-hydride elimination of an Et group, across the double-bond. The major products of this reaction were the 1-methylcyclopropyl complexes [Pt(C(CH₂)₂CH₃)Et(COD)] and [Pt(C(CH₂)₂CH₃)₂(COD)], the first examples of such complexes. Protonation of [Pt(L)(P—P)] resulted in a ring-opening reaction to form both the 2-substituted and 1-methyl allyl complexes, [Pt(ŋ³-CH₂CRCH₂)(P—P)]⁺ (R = ᶜPr, Me; P—P = Ph₂P(CH₂)₃PPh₂, ᵗBu₂PCH₂(o-C₆H₄)CH₂PᵗBu₂) and [Pt(ŋ³-CR₂CHCHMe)(P—P)]⁺ (R = cPr, Me; P—P = Ph₂P(CH₂)₃PPh₂, ᵗBuPCH₂(o-C₆H₄)CH₂PᵗBu₂). The analogous 1-methyl complexes were also formed from [Pt(L)(P—S)], wherein the alkene reacted with a hydride formed by the ortho-metallation of the P—S ligand. Computational models were used to investigate the formation of the allyl structures and it was found that the activation energy had a more significant effect than complex stability on product distributions. Complexes with β-chloroalkyl ligands [Pt(C(CH₂)₂CR₂Cl)Cl(L)₂] (R = CH₂, H, L = SEt₂, NCᵗBu, Py) were formed by the addition of Pt–Cl across the alkene double bond. Phosphine complexes were formed by the displacement of a ligand from cis–[Pt(C(CH₂)₂CR₂Cl)Cl(Py)₂] (R = CH₂, H). These are the first examples of stable Pt(II) β-haloalkyl complexes. It was found using computational models that the presence of cyclopropyl rings had a stabilising effect on these complexes.</p>

Platinum Complexes of Bicyclopropylidene and Related Ligands

<p>The coordination chemistry of the cyclopropyl-substituted alkenes, bicyclopropylidene (BCP) and methylenecyclopropane (MCP), with platinum was explored. A range of complexes with ŋ²-alkene ligands were synthesised by the displacement of a ligand, typically ethene, from a precursor complex. These complexes are [Pt(L)(P—P)] (L = BCP, MCP; P—P = Ph₂P(CH₂)₃PPh₂, Cy₂P(CH₂)₂PCy₂, ᵗBu₂P(CH₂)₂PᵗBu₂, ᵗBu₂PCH₂(o-C₆H₄)₂PᵗBu₂), [Pt(L)(P—S)] (L = BCP, MCP; P—S = ᵗBu₂PCH₂(o-₆H4)CH₂SᵗBu), [Pt(C₂H4)(L)(PR₃)] (L = BCP, MCP; PR₃ = PPh₃, PCy₃), [Pt(MCP)₂(PR₃)] (PR₃ = PPh₃, PCy₃) and [PtCl₂(L)(L′)] (L = BCP, MCP; L′ = Py, DMSO). These were the first examples of platinum complexes with ŋ²-BCP ligands, and the first bis-MCP Pt complexes. BCP underwent ring-opening reactions with both Pt(0) and Pt(II) complexes to form the 1,3-diene allylidenecyclopropane (ACP). The first transition metal complexes of ACP [Pt(ACP)(P—P)] (P—P = Ph₂P(CH₂)₃PPh₂, Cy₂P(CH₂)₂PCy₂, ᵗBu₂P(CH₂)₂PᵗBu₂) were synthesised. Some of these complexes rearranged to form ŋ²:σ²-metallacyclopentene complexes, the first instances of the formation of ŋ²:σ²-metallacyclopentene complexes from ŋ²:π-diene complexes. With MCP, the ring-opening reaction only occurred with [₂(COD)], as a result of the anti-Markovnikov addition of Pt–H, generated by the β-hydride elimination of an Et group, across the double-bond. The major products of this reaction were the 1-methylcyclopropyl complexes [Pt(C(CH₂)₂CH₃)Et(COD)] and [Pt(C(CH₂)₂CH₃)₂(COD)], the first examples of such complexes. Protonation of [Pt(L)(P—P)] resulted in a ring-opening reaction to form both the 2-substituted and 1-methyl allyl complexes, [Pt(ŋ³-CH₂CRCH₂)(P—P)]⁺ (R = ᶜPr, Me; P—P = Ph₂P(CH₂)₃PPh₂, ᵗBu₂PCH₂(o-C₆H₄)CH₂PᵗBu₂) and [Pt(ŋ³-CR₂CHCHMe)(P—P)]⁺ (R = cPr, Me; P—P = Ph₂P(CH₂)₃PPh₂, ᵗBuPCH₂(o-C₆H₄)CH₂PᵗBu₂). The analogous 1-methyl complexes were also formed from [Pt(L)(P—S)], wherein the alkene reacted with a hydride formed by the ortho-metallation of the P—S ligand. Computational models were used to investigate the formation of the allyl structures and it was found that the activation energy had a more significant effect than complex stability on product distributions. Complexes with β-chloroalkyl ligands [Pt(C(CH₂)₂CR₂Cl)Cl(L)₂] (R = CH₂, H, L = SEt₂, NCᵗBu, Py) were formed by the addition of Pt–Cl across the alkene double bond. Phosphine complexes were formed by the displacement of a ligand from cis–[Pt(C(CH₂)₂CR₂Cl)Cl(Py)₂] (R = CH₂, H). These are the first examples of stable Pt(II) β-haloalkyl complexes. It was found using computational models that the presence of cyclopropyl rings had a stabilising effect on these complexes.</p>

Total Synthesis of Resolvin T4

A total synthesis of resolvin T4 was achieved by connecting three intermediates by Wittig reactions. The enal in the C1–C10 part was constructed through reduction of a propargylic alcohol with Red-Al followed by oxidation. The enal moiety in the C11–C16 part was synthesized by a ring-opening reaction of a silyl epoxide followed by a Peterson elimination. The chiral centers at C7 and C13 were constructed by ruthenium-catalyzed asymmetric transfer hydrogenation.

Physical Properties of Thermally Crosslinked Fluorinated Polyimide and Its Application to a Liquid Crystal Alignment Layer

This study demonstrated the use of a thermally crosslinked polyimide (PI) for the liquid crystal (LC) alignment layer of an LC display (LCD) cell. Polyamic acid was prepared using 4,4′-oxydianiline (ODA) and 4,4′-(hexafluoroisopropylidene) diphthalic anhydride (6FDA). The 6FDA−ODA-based polyimide (PI) prepared by the thermal cyclic dehydration of the polyamic acid (PAA) was soluble in various polar solvents. After forming a thin film by mixing trifunctional epoxide [4-(oxiran-2-ylmethoxy)-N,N-bis(oxiran-2-ylmethyl)aniline] with the 6FDA−ODA-based PAA, it was confirmed that thermal curing at −110 °C caused an epoxy ring opening reaction, which could result in the formation of a networked polyimide not soluble in tetrahydrofuran. The crosslinked PI film showed a higher rigidity than the neat PI films, as measured by the elastic modulus. Furthermore, based on a dynamic mechanical analysis of the neat PI and crosslinked PI films, the glass transition temperatures (Tgs) were 217 and 339 °C, respectively, which provided further evidence of the formation of crosslinking by the addition of the epoxy reagent. After mechanical rubbing using these two PI films, an LC cell was fabricated using an anisotropic PI film as an LC alignment film. LC cells with crosslinked PI layers showed a high voltage holding ratio and low residual direct current voltage. This suggests that the crosslinked PI has good potential for use as an LC alignment layer material in advanced LCD technologies that require high performance and reliability.

Thiophene Ring-Opening Reactions III: One-Pot Synthesis and Antitumor Activity of 1,3,4-Thiadiazoline–Benzothiazolo[3,2-b]pyridazine Hybrids

Introduction: The preparation of model 6-chloro-5-nitrothieno[2,3-c]pyridazines incorporating (2'-halo-5'-nitrophenyl) entity is described. Interaction of these substrates with N'-(aryl)benzothiohydrazides, in the presence of triethylamine, followed a formal [4+1] annulation, furnishing the respective 1,3,4-thiadiazoline–benzothiazolo [3,2-b]pyridazine hybrids directly. This one-pot synthesis implies thiophene ring-opening and two consecutive intramolecular cyclizations. The structures of the synthesized new hybrids are supported by MS, NMR, and IR spectral data and further confirmed by single-crystal X-ray diffraction. These hybrids exhibit antiproliferative activity with notable selectivity against solid tumor cell lines (IC50: 4-18 μM). Aims: This study aimed at exploring the scope and applicability of thiophene ring-opening reaction towards the synthesis of new thiadiazoline–[fused]tricyclic conjugates. Background: α-Chloro-β-nitrothienopyridazine underwent ring-opening upon reacting with N'-(aryl)benzothiohydrazides generating 1,3,4-thiadiazoline–benzothiazolo[3,2-b]pyridazines. Objective: This new thiophene ring-opening reaction is applied to the one-pot synthesis of thiadiazoline–benzothiazolo[3,2-b]pyridazine couples. Method: A direct interaction of α-chloro-β-nitrothienopyridazine with N'-(aryl)benzothiohydrazide at room temperature for 1-2 h occurred. Result: α-Chloro-β-nitrothieno[2,3-c]pyridazines are suitable substrates for the facile synthesis of thiadiazoline–benzothiazolo[3,2-b]pyridazine hybrids. Conclusion: This novel ring-opening reaction proceeds via formal [4+1] annulation and provides a versatile approach to various conjugated and/or fused five-membered heterocycles.

Ring-Opening Fluorination of Bicyclic Azaarenes

We have discovered a ring-opening fluorination of bicyclic azaarenes. Upon treatment of bicyclic azaarenes such as pyrazolopyridines with electrophilic fluorinating agents, fluorination of the aromatic ring is followed by a ring-opening reaction. Although this overall trans-formation can be classified as an electrophilic fluorination of an aromatic ring, it is a novel type of fluorination that results in construction of tertiary carbon–fluorine bonds. The present protocol can be applied to a range of bicyclic azaarenes, tolerating azines and a variety of functional groups. Additionally, mechanistic studies and enantioselective fluorination have been examined.