Solvent‐free synthesis by using a vibratory ball mill (VBM) offers the chance to access new chemical reactivity, whilst reducing solvent waste and minimising reaction times. Herein, we report the ...core functionalisation of N,N’‐bis(2‐ethylhexyl)‐2,6‐dibromo‐1,4,5,8‐naphthalenetetracarboxylic acid (Br2‐NDI) by using Suzuki, Sonogashira and Buchwald–Hartwig coupling reactions. The products of these reactions are important building blocks in many areas of organic electronics including organic light‐emitting diodes (OLEDs), organic field‐effect transistors (OFETs) and organic photovoltaic cells (OPVCs). The reactions proceed in as little as 1 h, use commercially available palladium sources (frequently Pd(OAc)2) and are tolerant to air and atmospheric moisture. Furthermore, the real‐world potential of this green VBM protocol is demonstrated by the double Suzuki coupling of a monobromo(NDI) residue to a bis(thiophene) pinacol ester. The resulting dimeric NDI species has been demonstrated to behave as an electron acceptor in functioning OPVCs.
The solvent‐free synthesis of core‐functionalised naphthalene diimide (c‐NDI) residues in a vibratory ball mill is reported. Twenty‐one naphthalene diimide‐based products were produced by using Suzuki, Sonogashira and Buchwald‐Hartwig palladium coupling reactions, including dimeric diimide products that are constituents in functioning organic photovoltaic solar cells. These reactions are rapid (60 to 90 minutes), do not require additional heating, and are tolerant of air and atmospheric moisture.
We have previously shown that the thermolabile, cavity-creating p53 cancer mutant Y220C can be reactivated by small-molecule stabilizers. In our ongoing efforts to unearth druggable variants of the ...p53 mutome, we have now analyzed the effects of other cancer-associated mutations at codon 220 on the structure, stability, and dynamics of the p53 DNA-binding domain (DBD). We found that the oncogenic Y220H, Y220N, and Y220S mutations are also highly destabilizing, suggesting that they are largely unfolded under physiological conditions. A high-resolution crystal structure of the Y220S mutant DBD revealed a mutation-induced surface crevice similar to that of Y220C, whereas the corresponding pocket’s accessibility to small molecules was blocked in the structure of the Y220H mutant. Accordingly, a series of carbazole-based small molecules, designed for stabilizing the Y220C mutant, also bound to and stabilized the folded state of the Y220S mutant, albeit with varying affinities due to structural differences in the binding pocket of the two mutants. Some of the compounds also bound to and stabilized the Y220N mutant, but not the Y220H mutant. Our data validate the Y220S and Y220N mutants as druggable targets and provide a framework for the design of Y220S or Y220N-specific compounds as well as compounds with dual Y220C/Y220S specificity for use in personalized cancer therapy.
The carbazole compounds
(1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and
(1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of
...(1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damage-inducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with
and
being eligible candidates as "anticancer compounds" and "anticancer epi-compounds" and
a "damage-corrective" compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes.
A library of over twenty 5‐(2‐arylphenyl)‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐ones has been formed by a microwave‐mediated late‐stage palladium‐catalysed arylation of 1,4‐benzodiazepines using ...diaryliodonium salts. This can also be applied to nordazepam (7‐chloro‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one), the active metabolite of diazepam, and subsequent N‐alkylation and/or H/D exchange allows further diversification towards elaborated pharmaceuticals and their 3,3′‐deuterated analogues.
Combined photochemical arylation, “nuisance effect” (SNAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium‐throughput X‐ray protein–ligand ...structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho‐arylation of 2‐phenylpyridine gave five products resulting from mono‐ and bisarylations combined with SNAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.
Bottleneck breaker? C−H activation reactions coupled with “nuisance effect” SNAr processes have been designed to “lose control” in order to make discrete libraries for immediate testing, by X‐ray, against targets of interest. Although somewhat limited, these reactions could encourage others to try to reduce synthetic/work‐up bottlenecks and use crystallography as a more routine analytical format for drug discovery.
TC AC 28, 6-(1H-Indol-4-yl)-8-methoxy-1-methyl-4H-1,2,4triazolo4,3-a1,4benzodiazepine-4-acetic acid methyl ester, has been synthesized on a near-gram scale in seven steps with notable ...improvements in the reported poor-yielding last two steps enabling this key chemical probe compound to be available for researchers.
The widely used pentafluorosulfanyl group (SF5) was deployed as a bioisosteric replacement for a chloro-group in the benzodiazepine diazepam (Valium™). Reaction of ...2-amino-5-pentafluorosulfanyl-benzophenone with chloroacetyl chloride followed by hexamethylenetetramine, in the presence of ammonia, led to 7-sulfurpentafluoro-5-phenyl-1H-benzo1,4diazepin-2(3H)-one (2c). The latter was able to undergo a Pd-catalysed ortho-arylation, demonstrating that these highly fluorinated benzodiazepines can be further modified to form more complicated scaffolds. The replacement of Cl by the SF5 group, led to a loss of potency for potentiating GABAA receptor activation, most likely because of a lost ligand interaction with His102 in the GABAA receptor α subunit.
Dedicated to Professor Jonathan Williams, an inspirational and humble pioneer, a colleague and mentor in chemistry.
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This thesis focuses on developing efficient, atom-economic synthesis routes for functionalised 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one libraries. 1,4-Benzodiazepines (BZDs) are often referred ...to as “privileged scaffolds” due to their important biological activities; therefore, finding new efficient methods for synthesising such analogues is highly desirable in pharmaceutical and medicinal research. Chapter 1 introduces the project detailing the biological importance and applications of BZDs. The classical synthetic routes towards BZDs and some of the limitations for efficient and rapid BZD-based library synthesis, followed by the aims of the project. Chapter 2 presents a late-stage C-H activation method for synthesising ortho-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, including a library of over twenty novel analogues. The microwave-mediated palladium catalysed arylation method is also applicable to nordazepam (7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one), the active metabolite of diazepam. Further diversification of the compounds is achieved by N-alkylation and/or H/D exchange, which affords elaborated pharmaceuticals. Chapter 3 describes an alternative catalytic visible light-mediated photoredox method for ortho-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones. The protocol uses aryldiazonium salts in refluxing methanol and showcases an interesting phenomenon known as the “nuisance effect” with 2- or 4-fluorobenzenediazonium salts. It results in both fluoroaryl and methoxyaryl- products, the latter result from a nucleophilic aromatic substitution (SNAr) on the fluorobenzenediazonium salt (nuisance effect). The results from biological tests of the benzodiazepine libraries against GABAA receptors indicated that the C-7 substituent is vital for activities in GABA and only the 7-chloro-benzodiazepines show any reasonable activities, although ortho arylation is detrimental to bioactivity. A computational DFT analysis of the reaction mechanism from our collaborators is also discussed in the Chapter. Chapter 4 contains a brief overview of C-H functionalisation protols. Moreover, in this Chapter, the photoredox C-H activation method combined with the nuisance effect are extended to other privileged scaffolds. This Chapter describes the synthesis of small libraries of 2-phenylpyridines and 1-phenyl-2-pyrrolidinones. The nuisance effect proves to be effective in creating small arrays of compounds from a single reaction and in X-ray screening arrays for biological testing. A number of 1-phenyl-2-pyrrolidinone analogues display promising biological activities towards NUDT7, a peroxisomal coenzyme A diphosphatase of current interest. Chapter 5 focuses on the synthesis of a series of N1-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones. The N-arylation occurs in one-step using a single 1,4-benzodiazepine precursor with unsymmetrical diaryliodonium salts in aqueous ammonia as a base. Chapter 6 reports the scale-up synthesis of 6-(1H-indol-4-yl)-8-methoxy-1-methyl-4H-1,2,4triazolo4,3-a1,4benzodiazepine-4-acetic acid methyl ester, TC-AC-28. This BZD derivative is a highly selective bromo and extra terminal (BET) bromodomain inhibitor and a useful epigenetic tool compound. The near gram-scale, seven-step synthesis of this key chemical probe compound enabled it to be available for researchers through Tocris, one of our industry sponsors, and where I spent 3 months as part of my CASE award. Chapter 7 concludes the thesis and concentrates on future directions.
Abstract
A library of
N
1-arylated 5-phenyl-1,3-dihydro-2
H
-1,4-benzodiazepin-2-ones has been synthesized starting with unsymmetrical diaryliodonium salts using aqueous ammonia as a base. This can ...also be applied to a similar 1,3,4-benzotriazepin-2-one derivative.
This thesis focuses on developing efficient, atom-economic synthesis routes for functionalised 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one libraries. 1,4-Benzodiazepines (BZDs) are often referred ...to as “privileged scaffolds” due to their important biological activities; therefore, finding new efficient methods for synthesising such analogues is highly desirable in pharmaceutical and medicinal research. Chapter 1 introduces the project detailing the biological importance and applications of BZDs. The classical synthetic routes towards BZDs and some of the limitations for efficient and rapid BZD-based library synthesis, followed by the aims of the project. Chapter 2 presents a late-stage C-H activation method for synthesising ortho-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, including a library of over twenty novel analogues. The microwave-mediated palladium catalysed arylation method is also applicable to nordazepam (7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one), the active metabolite of diazepam. Further diversification of the compounds is achieved by N-alkylation and/or H/D exchange, which affords elaborated pharmaceuticals. Chapter 3 describes an alternative catalytic visible light-mediated photoredox method for ortho-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones. The protocol uses aryldiazonium salts in refluxing methanol and showcases an interesting phenomenon known as the “nuisance effect” with 2- or 4-fluorobenzenediazonium salts. It results in both fluoroaryl and methoxyaryl- products, the latter result from a nucleophilic aromatic substitution (SNAr) on the fluorobenzenediazonium salt (nuisance effect). The results from biological tests of the benzodiazepine libraries against GABAA receptors indicated that the C-7 substituent is vital for activities in GABA and only the 7-chloro-benzodiazepines show any reasonable activities, although ortho arylation is detrimental to bioactivity. A computational DFT analysis of the reaction mechanism from our collaborators is also discussed in the Chapter. Chapter 4 contains a brief overview of C-H functionalisation protols. Moreover, in this Chapter, the photoredox C-H activation method combined with the nuisance effect are extended to other privileged scaffolds. This Chapter describes the synthesis of small libraries of 2-phenylpyridines and 1-phenyl-2-pyrrolidinones. The nuisance effect proves to be effective in creating small arrays of compounds from a single reaction and in X-ray screening arrays for biological testing. A number of 1-phenyl-2-pyrrolidinone analogues display promising biological activities towards NUDT7, a peroxisomal coenzyme A diphosphatase of current interest. Chapter 5 focuses on the synthesis of a series of N1-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones. The N-arylation occurs in one-step using a single 1,4-benzodiazepine precursor with unsymmetrical diaryliodonium salts in aqueous ammonia as a base. Chapter 6 reports the scale-up synthesis of 6-(1H-indol-4-yl)-8-methoxy-1-methyl-4H-1,2,4triazolo4,3-a1,4benzodiazepine-4-acetic acid methyl ester, TC-AC-28. This BZD derivative is a highly selective bromo and extra terminal (BET) bromodomain inhibitor and a useful epigenetic tool compound. The near gram-scale, seven-step synthesis of this key chemical probe compound enabled it to be available for researchers through Tocris, one of our industry sponsors, and where I spent 3 months as part of my CASE award. Chapter 7 concludes the thesis and concentrates on future directions.
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