The current development in the field describes strategies that have never been used before for the design of hybrid anticancer drugs. The information currently available and described in this section allows us to identify the main parameters required to design such molecules. It also provides a clear view of the future directions that must be explored for the successful development and discovery of useful hybrid anticancer drugs.
We located the binding sites of doxorubicin (DOX) and N-(trifluoroacetyl) doxorubicin (FDOX) with bovine serum albumin (BSA) and human serum albumins (HSA) at physiological conditions, using constant protein concentration and various drug contents. FTIR, CD and fluorescence spectroscopic methods as well as molecular modeling were used to analyse drug binding sites, the binding constant and the effect of drug complexation on BSA and HSA stability and conformations. Structural analysis showed that doxorubicin and N-(trifluoroacetyl) doxorubicin bind strongly to BSA and HSA via hydrophilic and hydrophobic contacts with overall binding constants of K
DOX-BSA = 7.8 (±0.7)×103 M−1, K
FDOX-BSA = 4.8 (±0.5)×103 M−1 and K
DOX-HSA = 1.1 (±0.3)×104 M−1, K
FDOX-HSA = 8.3 (±0.6)×103 M−1. The number of bound drug molecules per protein is 1.5 (DOX-BSA), 1.3 (FDOX-BSA) 1.5 (DOX-HSA), 0.9 (FDOX-HSA) in these drug-protein complexes. Docking studies showed the participation of several amino acids in drug-protein complexation, which stabilized by H-bonding systems. The order of drug-protein binding is DOX-HSA > FDOX-HSA > DOX-BSA > FDOX>BSA. Drug complexation alters protein conformation by a major reduction of α-helix from 63% (free BSA) to 47–44% (drug-complex) and 57% (free HSA) to 51–40% (drug-complex) inducing a partial protein destabilization. Doxorubicin and its derivative can be transported by BSA and HSA in vitro.
Current advances show that molecular hybrids of biologically active molecules can lead to powerful therapeutics. Natural products play a key role in this field. It is also believed that toxin hybrids present a great opportunity for future progress and should be further explored. Furthermore, the synthesis of hybrid organometallics should be systematically studied as it can lead to potent drugs. The crucial requirement for growth still remains the efficacy of synthesis. Hence, the development of efficient synthetic methods allowing rapid access to diverse series of hybrids must be further investigated by researchers.
BackgroundAmaryllidaceae alkaloids (AAs) are a large group of plant-specialized metabolites displaying an array of biological and pharmacological properties. Previous investigations on AA biosynthesis have revealed that all AAs share a common precursor, norbelladine, presumably synthesized by an enzyme catalyzing a Mannich reaction involving the condensation of tyramine and 3,4-dihydroxybenzaldehyde. Similar reactions have been reported. Specifically, norcoclaurine synthase (NCS) which catalyzes the condensation of dopamine and 4-hydroxyphenylacetaldehyde as the first step in benzylisoquinoline alkaloid biosynthesis.ResultsWith the availability of wild daffodil (Narcissus pseudonarcissus) database, a transcriptome-mining search was performed for NCS orthologs. A candidate gene sequence was identified and named norbelladine synthase (NBS). NpNBS encodes for a small protein of 19 kDa with an anticipated pI of 5.5. Phylogenetic analysis showed that NpNBS belongs to a unique clade of PR10/Bet v1 proteins and shared 41% amino acid identity to opium poppy NCS1. Expression of NpNBS cDNA in Escherichia coli produced a recombinant enzyme able to condense tyramine and 3,4-DHBA into norbelladine as determined by high-resolution tandem mass spectrometry.ConclusionsHere, we describe a novel enzyme catalyzing the first committed step of AA biosynthesis, which will facilitate the establishment of metabolic engineering and synthetic biology platforms for the production of AAs.Electronic supplementary materialThe online version of this article (10.1186/s12870-018-1570-4) contains supplementary material, which is available to authorized users.
N,N-((Butyloxy)propyl)amino diacetic acid is an amphoteric surfactant of the glycinate family. The synthesis of this glycinate was achieved via the ester route to obtain a pure compound. The infrared (IR) spectra of the aqueous solutions of this compound were obtained in the pH range 0.2-14 in order to determine the ionic distribution of the molecule as a function of pH. After subtracting the water bands in the IR spectra, factor analysis (FA) was used to separate the spectra of the ionic species and determine their abundance. The pKa's were retrieved from the volumetric titration as a function of pH. The values were used to calculate the volumetric abundance of each ionic species as a function of pH. The distribution curves thus obtained were compared with the normalized distribution curves obtained from the IR data. There is a good agreement between the two curves. The following species were obtained for the glycinate in water: the cation (pH 0-3.4), the zwitterion (pH 0-5.4), the monocarboxylate (pH 1-12), and the dicarboxylate (pH 7-14).
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