110117-83-4Relevant articles and documents
Biocatalysts from cyanobacterial hapalindole pathway afford antivirulent isonitriles against MRSA
Bunn, Brittney M,Xu, Mizhi,Webb, Chase M,Viswanathan, Rajesh
, (2021)
Abstract: The emergence of resistance to frontline antibiotics has called for novel strategies to combat serious pathogenic infections. Methicillin-resistant Staphylococcus aureus [MRSA] is one such pathogen. As opposed to traditional antibiotics, bacteriostatic anti-virulent agents disarm MRSA, without exerting pressure, that cause resistance. Herein, we employed a thermophilic Thermotoga maritima tryptophan synthase (TmTrpB1) enzyme followed by an isonitrile synthase and Fe(II)-α-ketoglutarate-dependent oxygenase, in sequence as biocatalysts to produce antivirulent indole vinyl isonitriles. We report on conversion of simple derivatives of indoles to their C3-vinyl isonitriles, as the enzymes employed here demonstrated broader substrate tolerance. In toto, eight distinct L-Tryptophan derived α-amino acids (7) were converted to their bioactive vinyl isonitriles (3) by action of an isonitrile synthase (WelI1) and an Fe(II)-α-ketoglutarate-dependent oxygenase (WelI3) yielding structural variants possessing antivirulence against MRSA. These indole vinyl isonitriles at 10 μg/mL are effective as antivirulent compounds against MRSA, as evidenced through analysis of rabbit blood hemolysis assay. Based on a homology modelling exercise, of enzyme-substrate complexes, we deduced potential three dimensional alignments of active sites and glean mechanistic insights into the substrate tolerance of the Fe(II)-α-ketoglutarate-dependent oxygenase. Graphic abstract: [Figure not available: see fulltext.]
Pentapeptides for the treatment of small cell lung cancer: Optimisation by Nind-alkyl modification of the tryptophan side chain
Haitham Abusara, Osama,Freeman, Sally,Aojula, Harmesh Singh
, p. 221 - 232 (2017/06/08)
The pentapeptide, tert-Prenyl4th-NH2 (DMePhe-DTrp-Phe-DTrp(N-tert-prenyl)-Leu-NH2), has recently been reported by our group to exhibit properties of substance P (SP) antagonist G against small cell lung cancer (SCLC). In this study, we undertook a systematic structure activity investigation to optimise this lead compound to improve its in vitro anti-tumour activity and biocompatibility. A series of D-tryptophan (D-Trp) derivatives were synthesised, with a range of aliphatic N-alkyl chains (methyl to pentyl) on the indole nitrogen (Nind). These were incorporated into the pentapeptide sequence by substitution of the Nind-tert-prenylated D-Trp 4th residue with the Nind-alkylated D-Trp derivatives. These pentapeptides were significantly more potent than tert-Prenyl4th-NH2, with the Nind-butyl modification generating the most cytotoxic peptides. Compared to tert-Prenyl4th-NH2, a single butyl modification on the 4th D-Trp residue (Butyl4th-NH2) showed a ～3 fold enhancement in cytotoxicity in either the chemo-naive H69 or the DMS79 (originating from a patient treated with chemotherapeutics and radiation therapy) SCLC cell lines. In addition, the di-butylated sequence on the 2nd and 4th D-Trp residues (Butyl2nd,4th-NH2) gave ～4.5 times higher cytotoxicity against the H69 cell line and a ～2 fold increase against the DMS79 cell line, compared to tert-Prenyl4th-NH2. The favoured position for butyl modification was the 4th D-Trp residue, as the Butyl2nd-NH2 peptide gave lower cytotoxicity on both cell lines. Butylated peptide sequences, when exposed to neat mouse plasma for 24 h at 37 °C, were found to resist degradation with >80% remaining intact compared to ～58% for tert-Prenyl4th-NH2. The degradation pathway in plasma occurs via de-amidation of the C-terminus, confirmed by mass spectrometry and RP-HPLC analysis. The butyl modification also conferred resistance to metabolism when tested using S9 liver fraction from mouse. The optimum analogue responsive against the DMS79 cell line was the Butyl4th-NH2 pentapeptide, which revealed a concentration dependent increase in apoptosis: the level of late apoptotic cells rose from ～36% at 2 μM to ～96% at 6 μM, as determined by flow cytometry, compared to the unmodified peptide that showed no such effect. Concluding, the butyl substitutions offered the best perspective for high cytotoxicity, induction of apoptosis and metabolic compatibility thereby comprising an improved broad spectrum SP antagonist candidate for treatment of SCLC.
Palladium-N-heterocyclic carbene (NHC)-catalyzed asymmetric synthesis of indolines through regiodivergent C(sp3)-H activation: Scope and DFT study
Katayev, Dmitry,Larionov, Evgeny,Nakanishi, Masafumi,Besnard, Cline,Kündig, E. Peter
supporting information, p. 15021 - 15030 (2015/02/19)
Two bulky, chiral, monodentate N-heterocyclic carbene ligands were applied to palladium-catalyzed asymmetric C-H arylation to incorporate C(sp3)-H bond activation. Racemic mixtures of the carbamate starting materials underwent regiodivergent reactions to afford different trans-2,3- substituted indolines. Although this CAr-Calkyl coupling requires high temperatures (140-160°C), chiral induction is high. This regiodivergent reaction, when carried out with enantiopure starting materials, can lead to single structurally different enantiopure products, depending on the catalyst chirality. The C-H activation at a tertiary center was realized only in the case of a cyclopropyl group. No C-H activation takes place alpha to a tertiary center. A detailed DFT study is included and analyses of methyl versus methylene versus methine C-H activation is used to rationalize experimentally observed regio- and enantioselectivities.
