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Distamycin‐NA: A DNA analog with an aromatic heterocyclic polyamide backbone. Part 2. Solid‐phase synthesis of distamycin‐NAs containing the nucleobase uracil: Unexpected solvent participation in the coupling step
Author(s) -
Sauter Guido,
Leumann Christian
Publication year - 1998
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19980810512
Subject(s) - chemistry , amide , tetramer , acetamide , stereochemistry , nucleobase , dna , solid phase synthesis , solvent , combinatorial chemistry , peptide , organic chemistry , biochemistry , enzyme
The synthesis of the Fmoc‐protected amino acid 2 is presented. First attempts of amide‐bond formation to the homodimer 4 in solution showed only poor coupling yields indicative for the low reactivity of the amino and carboxy groups in the building blocks 1 and 2 , respectively ( Scheme 1 ). Best coupling yields were found using dicyclohexylcarbodiimide (DCC) without any additive. The oligomerization of building block 2 adopting the Fmoc ((9 H ‐fluoren‐9‐ylmethoxy)carbonyl) solid‐phase synthesis yielded a mixture of N‐terminal‐modified distamycin‐NA derivatives. By combined HPLC and MALDI‐TOF‐MS analysis, the N‐terminal functional groups could be identified as acetamide and N , N ‐dimethylformamidine functions, arising from coupling of the N‐terminus of the growing chain with residual AcOH or DCC‐activated solvent DMF. An improved preparation of building block 2 and coupling protocol led to the prevention of the N‐terminal acetylation. However, ‘amidination’ could not be circumvented. A thus isolated tetramer of 2 , containing a lysine unit at the C‐terminus and a N , N ‐dimethylformamidine‐modified N‐terminus, not unexpectedly, showed no complementary base pairing to DNA and RNA, as determined by standard UV‐melting‐curve analysis.