PubMed · 14950706
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1952-04-20. [Mintacol solution].. https://pubmed.ncbi.nlm.nih.gov/14950706/
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Chemical ligation approaches facilitate the chemoselective assembly of unprotected peptides in aqueous solution. Here, two photolabile auxiliaries are described that enlarge the applicability of native chemical ligation to non-cysteine targets. The auxiliaries, designed to allow reaction with thioester peptides, generate an amide bond between the two initial fragments. The o-nitrobenzyl tertiary benzylamide that is formed at the ligation junction can be transformed into a native amide group under mild photolysis conditions. The veratryl auxiliary was found to be excessively labile during peptide purification and ligation. However, the auxiliary based on the o-nitrobenzyl group shows all the necessary properties for a general application in routine peptide and protein synthesis. In addition, the auxiliary linked to the N-terminus can be efficiently photolyzed, suggesting a new approach for the generation of photocaged amines. Synthesis, solid phase introduction onto peptide chains, ligation properties and photolysis in water are described, and a careful study of compatibility of the method with potentially fragile peptide side chains is reported.
Photodirected oligonucleotide synthesis uses either direct or indirect light-dependent 5'-deprotection. Both have been reported to give lower stepwise synthetic yields than conventional methods. The deficiency appears to be due to incomplete deprotection at the oligonucleotide 5'-position and, additionally in the case where photodirection is indirect and uses photogenerated photoacid to effect 5'-detritylation, the depurinating effects of strong acid. We have developed novel photosensitive-2-nitrobenzyl esters that on irradiation with near UV light generate alpha-chloro-substituted acetic acids, such as trichloroacetic acid, which are widely and successfully used in conventional solid-phase oligonucleotide synthesis. alpha-Phenyl-4,5-dimethoxy-2-nitrobenzyltrichloroacetate and alpha-phenyl-4,5-dimethoxy-2,6-dinitrobenzyltrichloroacetate showed appropriate photochemical characteristics and were used for photodirected synthesis of a variety of oligonucleotides, including (T)(5), TATAT, TGTGT, (T)(10), (AT)(5), (CT)(5) (GT)(5), and (TGCAT)(2) on a modified Millipore Expedite DNA synthesizer. The outcomes were compared with those obtained by use of directly added trichloroacetic acid (conventional synthesis). The stepwise yields for the two methods were essentially identical.
Inhibition of growth of the yeast Saccharomyces cerevisiae (Cmiz, the minimum concentration that produced a clear inhibition zone within 12 h) for 24 nitroaromatic compounds was investigated and a quantitative structure-activity relationship (QSAR) developed based on hydrophobicity expressed as the l-octanol/water partition coefficient in logarithm form, log K(ow), electrophilicity based on the energy of the lowest unoccupied orbital (E(lumo)). All nitrobenzene derivatives exhibited enhanced reactive toxicity than baseline. The toxicities of mono-nitrobenzenes and di-nitrobenzenes were elicited by different mechanisms of toxic action. For mono-nitro-derivatives, both significant log K(ow) based and strong E(lumo)-dependent relationships were observed indicating that their toxicities were affected both by the penetration process and the interaction with target sites of interaction. The toxicities of di-nitrobenzenes were greater than mono-nitrobenzenes and no log K(ow)-dependent but highly significant E(lumo)-based relationship was obtained. This suggests that toxicity of di-nitrobenzenes was highly electrophilic and involved mainly their in vivo electrophilic interaction with biomacromolecules. In an effort to model the elevated toxicity of all nitrobenzenes, a response-surface analysis was performed and this resulted in a highly predictive two-variable QSAR without reference to their exact mechanisms (Cmiz = 0.41 log K(ow) - 0.89 E(lumo) - 0.46, r2 = 0.87, Q2 = 0.86, n = 24).