Synthesis, experimental andin silicostudies ofN-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids

Abstract

Recently, fluorenylmethoxycarbonyl (Fmoc) amino acids (e.g. Fmoc–tyrosine or Fmoc–phenylalanine) have attracted growing interest in biomedical research and industry, with special emphasis directed towards the design and development of novel effective hydrogelators, biomaterials or therapeutics. With this in mind, a systematic knowledge of the structural and supramolecular features in recognition of those properties is essential. This work is the first comprehensive summary of noncovalent interactions combined with a library of supramolecular synthon patterns in all crystal structures of amino acids with the Fmoc moiety reported so far. Moreover, a new Fmoc‐protected amino acid, namely, 2‐{[(9H‐fluoren‐9‐ylmethoxy)carbonyl](methyl)amino}‐3‐{4‐[(2‐hydroxypropan‐2‐yl)oxy]phenyl}propanoic acid or N‐fluorenylmethoxycarbonyl‐O‐tert‐butyl‐N‐methyltyrosine, Fmoc‐N‐Me‐Tyr(t‐Bu)‐OH, C29H31NO5, was successfully synthesized and the structure of its unsolvated form was determined by single‐crystal X‐ray diffraction. The structural, conformational and energy landscape was investigated in detail by combined experimental and in silico approaches, and further compared to N‐Fmoc‐phenylalanine [Draper et al. (2015). CrystEngComm, 42, 8047–8057]. Geometries were optimized by the density functional theory (DFT) method either in vacuo or in solutio. The polarizable conductor calculation model was exploited for the evaluation of the hydration effect. Hirshfeld surface analysis revealed that H…H, C…H/H…C and O…H/H…O interactions constitute the major contributions to the total Hirshfeld surface area in all the investigated systems. The molecular electrostatic potentials mapped over the surfaces identified the electrostatic complementarities in the crystal packing. The prediction of weak hydrogen‐bonded patterns via Full Interaction Maps was computed. Supramolecular motifs formed via C—H…O, C—H…π, (fluorenyl)C—H…Cl(I), C—Br…π(fluorenyl) and C—I…π(fluorenyl) interactions are observed. Basic synthons, in combination with the Long‐Range Synthon Aufbau Modules, further supported by energy‐framework calculations, are discussed. Furthermore, the relevance of Fmoc‐based supramolecular hydrogen‐bonding patterns in biocomplexes are emphasized, for the first time.

A Global Review on Short Peptides: Frontiers and Perspectives

“…Supramolecular chemistry (‘‘chemistry beyond the molecule’’) is a bottom-up approach to the formation of well-ordered structures in the nano- (and the micro-) scale. Their adaptable, controllable, self-healing, and bio-physico-chemical stimuli-responsive properties induced via non-covalent interactions (electrostatic, hydrogen bonding, π–π stacking, van der Waals or hydrophobic) are highly appreciated [ 123 , 127 , 128 , 129 , 130 , 131 , 132 ]. They have the dynamic nature and provide a firm basis for the structure and functioning of living systems.…”

“…Modified peptides with aromatic amino acids or functionalized side chains (e.g., Fmoc) promote additional stacking interactions ( Figure 4 ), which are helpful in the self-assembly process. Peptide-based bio-functional supramolecular materials (nanomedicines, hydrogels, drug delivery vehicles, gene or drug carriers, biomimetic-cell culture scaffolds, tissue-engineering systems, biosensors, emulsifiers, peptidomimetic antibiotics, bioimaging nanoprobes, three-dimensional (3D) bioprinting inks, vaccine adjuvants) have low toxicity and high biocompatibility and are useful in various applications, like drug delivery, tissue engineering, immunology, cancer therapy, and stem cell culture [ 38 , 95 , 101 , 131 , 132 , 133 , 134 , 135 , 136 ]. Supramolecular nanotherapeutics have better stability and efficacy, which helps to overcome problems related to peptide poor biostability and short plasma half-life.…”

Peptide-Drug Conjugates: A New Hope for Cancer Management

“…Peptides, as constituents of proteins, are promising, safe, and effective anti-cancer therapeutics and are engaged in nearly all biological functions. Short peptides do not induce an undesired autoimmune response; they have high selectivity and specificity, are able to cross cell membranes, and penetrate tumors more efficiently [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Herein, applications of peptide-drug conjugates, their basic components, conjugation chemistry, release action, and different stages of their clinical development, regulatory procedures, and other challenges are presented.…”

Supramolecular synthon hierarchy in cyclopropyl-containing peptide-derived compounds

“…These studies fit into the mainstream of our ongoing project that concentrates on supramolecular exploration and bioactivity of peptide-based molecules. 37,38,44–82…”