The main transporter for biotin is sodium dependent multivitamin transporter (SMVT), which is overexpressed in various aggressive cancer cell lines such as ovarian (OV 2008, ID8), leukemia (L1210FR), mastocytoma (P815), colon (Colo-26), breast (4T1, JC, MMT06056), renal (RENCA, RD0995), and lung (M109) cancer cell lines. Furthermore, its overexpression was found higher to that of folate receptor. Therefore, biotin demand in the rapidly growing tumors is higher than normal tissues. Several biotin conjugated organic molecules has been reported here for selective delivery of the drug in cancer cell. Biotin conjugated molecules are showing higher fold of cytotoxicity in biotin positive cancer cell lines than the normal cell. Nanoparticles and polymer surface modified drugs and biotin mediated cancer theranostic strategy was highlighted in this review. The cytotoxicity and selectivity of the drug in cancer cells has enhanced after biotin conjugation.(Eur J Med Chem. 2018 Feb 10;145:206-223. )
The rise of resistant bacteria has prompted the search for new antimicrobial agents. Antimicrobial membrane lytic peptides have potential as future microbial agents due to their novel mode of action. Recently conjugation of a fatty acid to antimicrobial peptides has been explored as a method to modulate the activity and selectivity of the peptide. Our work further explores these phenomena by testing two peptides, YGAAKKAAKAAKKAAKAA (AKK) and LKKLLKLLKLLKL (LKK), conjugated to fatty acids of varying length for their activity, structure, solution assembly properties and the ability to bind model membranes. We found that increasing the length of fatty acids conjugated to peptide AKK, up to a 16 carbons in length, increases the antimicrobial activity. Peptide AKK appears to lose activity when the minimal active concentration is higher than the critical miscelle concentration (CMC) of the molecule. Thus, if the CMC of the peptide conjugate is too low the activity is lost. Peptide LKK has no activity when conjugated to lauric acid and appears to aggregate at very low concentrations. Conjugation of AKK with a fatty acid increases its affinity to model supported lipid membranes. It appears that the increased hydrophobic interaction imparted by the fatty acid increases the affinity of the peptide to the surface thus increasing its activity. At concentrations above the CMC, solution self-assembly inhibits binding of the peptide to cell membranes.
A series of 21 new amino alcohol fused Spirochromone conjugates have been synthesized, characterized with analytical data and evaluated their antimycobacterial activity against Mycobacterium tuberculosis (virulent strain H37Rv) in vitro. Some of the compounds exerted significant inhibition, in particular, compound 4f found to be the most potent derivative exhibiting MIC = 3.13 μg/mL.
Although recent methods for targeted drug delivery have addressed many of the existing problems of cancer therapy associated with undesirable side effects, significant challenges remain that have to be met before they find significant clinical relevance. One such area is the delicate chemical bond that is applied to connect a cytotoxic drug with targeting moieties like antibodies or peptides. Here we describe a novel platform that can be utilized for the preparation of drug–carrier conjugates in a site-specific manner, which provides excellent versatility and enables triggered release inside cancer cells. Its key feature is a cleavable doxorubicin–octreotide bioconjugate that targets overexpressed somatostatin receptors on tumor cells, where the coupling between the two components was achieved through the first cleavable disulfide-intercalating linker. The tumor targeting ability and suppression of adrenocorticotropic hormone secretion in AtT-20 cells by both octreotide and the doxorubicin hybrid were determined via a specific radioimmunoassay. Both substances reduced the hormone secretion to a similar extent, which demonstrated that the tumor homing peptide is able to interact with the relevant cell surface receptors after the attachment of the drug. Effective drug release was quickly accomplished in the presence of the physiological reducing agent glutathione. We also demonstrate the relevance of this scaffold in biological context in cytotoxicity assays with pituitary, pancreatic, and breast cancer cell lines.(Mol Pharm. 2015 Dec 7;12(12):4290-300. )
The advent of click chemistry has had a profound influence on almost all branches of chemical science. This is particularly true of radiochemistry and the synthesis of agents for positron emission tomography (PET), single photon emission computed tomography (SPECT), and targeted radiotherapy. The selectivity, ease, rapidity, and modularity of click ligations make them nearly ideally suited for the construction of radiotracers, a process that often involves working with biomolecules in aqueous conditions with inexorably decaying radioisotopes. In the following pages, our goal is to provide a broad overview of the first 10 years of research at the intersection of click chemistry and radiochemistry. The discussion will focus on four areas that we believe underscore the critical advantages provided by click chemistry: (i) the use of prosthetic groups for radiolabeling reactions, (ii) the creation of coordination scaffolds for radiometals, (iii) the site-specific radiolabeling of proteins and peptides, and (iv) the development of strategies for in vivo pretargeting. Particular emphasis will be placed on the four most prevalent click reactions—the Cu-catalyzed azide-alkyne cycloaddition (CuAAC), the strain-promoted azide-alkyne cycloaddition (SPAAC), the inverse electron demand Diels-Alder reaction (IEDDA), and the Staudinger ligation—although less well-known click ligations will be discussed as well. Ultimately, it is our hope that this review will not only serve to educate readers but will also act as a springboard, inspiring synthetic chemists and radiochemists alike to harness click chemistry in even more innovative and ambitious ways as we embark upon the second decade of this fruitful collaboration.
Bioorthogonal click ligations satisfy all of the requirements of standard click reactions but are also inert within biological systems. Not surprisingly, these reactions are hard to come by, yet a handful (most notably the Staudinger ligation, the strain-promoted azide–alkyne cycloaddition reaction, and the inverse electron demand Diels–Alder cycloaddition) have been developed and proven powerful in the hands of chemical biologists, biochemists, and biomedical scientists (Bioconjug Chem. 2016 Dec 21;27(12):2791-2807.)
Carbamate-bearing molecules play an important role in modern drug discovery and medicinal chemistry. Organic carbamates (or urethanes) are structural elements of many approved therapeutic agents. Structurally, the carbamate functionality is related to amide-ester hybrid features and, in general, displays very good chemical and proteolytic stabilities. Carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry. This is mainly due to their chemical stability and capability to permeate cell membranes. Another unique feature of carbamates is their ability to modulate inter- and intramolecular interactions with the target enzymes or receptors. The carbamate functionality imposes a degree of conformational restriction due to the delocalization of nonbonded electrons on nitrogen into the carboxyl moiety. In addition, the carbamate functionality participates in hydrogen bonding through the carboxyl group and the backbone NH. Therefore, substitution on the O- and N-termini of a carbamate offers opportunities for modulation of biological properties and improvement in stability and pharmacokinetic properties. Carbamates have been manipulated for use in the design of prodrugs as a means of achieving first-pass and systemic hydrolytic stability. Carbamate derivatives are widely represented in agricultural chemicals, such as pesticides, fungicides, and herbicides. They play a major role in the chemical and paint industry as starting materials, intermediates, and solvents. Furthermore, organic carbamates serve a very important role as optimum protecting groups for amines and amino acids in organic synthesis and peptide chemistry.
Peptide-based molecules are an important starting point for drug discovery, especially in the design of enzyme inhibitors. Because of their high affinity and specificity toward biological functions, peptide-based molecules also serve as valuable research tools. However, the poor in vivo stability, inadequate pharmacokinetic properties, and low bioavailability have generally limited their broader utility. Hence, a variety of peptide mimics are being developed to improve drug-like character along with increased potency, target specificity, and longer duration of action. To this end, several classes of peptidomimetics are tailored by replacing the native amide bond with unnatural linkages such as retro-amide, urea, carbamate, and heterocycles as peptide bond surrogates. These functionalities confer metabolic stability toward aminopeptidases, the enzymes involved in the metabolism of peptide-like drugs. The carbamate’s emerging role in medicinal chemistry is also due to its chemical stability and to its capability to increase permeability across cellular membranes. These attributes of organic carbamates have been exploited in drug design. As a result, the carbamate motif is becoming the choice for peptide bond surrogates.
Over the years, a variety of carabamates have been prepared by utilizing the Hofmann rearrangement of amides, the Curtius rearrangement of acyl azides,the reductive carbonylation of nitroaromatics, the carbonylation of amines, the reaction of alcohols with isocyanates, and carbon dioxide alkylation.The Hofmann rearrangement is well-recognized as a useful method to convert primary carboxamides to amines or carbamates, characterized by the reduction of one carbon in the structure.Much effort has been devoted to the development of modified reagents to optimize the Hofmann rearrangement since the classical method for this transformation, involving the use of an alkaline solution of bromine, is unsatisfactory and unreliable. A variety of oxidants and bases have been proposed as modified agents, e.g., iodine(III) reagents such as PhI(OAc)2, MeOBr, NBS-CH3ONa, NBS-KOH, lead tetraacetate, and benzyltrimethylammonium tribromide. These modified methods, however, require more than 1 equiv or an excess amount of the oxidizing reagent, which is not very convenient.The Curtius rearrangement is the thermal decomposition of acyl azides into the isocyanate intermediate. This method is widely employed in the transformation of carboxylic acids into carbamates and ureas. Acyl azides are usually prepared from carboxylic acid derivatives such as acyl chlorides, mixed anhydrides, and hydrazides. Subsequent isocyanate intermediates can be trapped by a variety of nucleophiles to provide the carbamate derivatives. The acid chloride method is not suitable for acid-sensitive functionalities. One-pot transformations of carboxylic acids into carbamates avoids the isolation of unstable acyl azides. However, protocols involving the use of diphenylphosphoryl azide (DPPA) for the one-pot Curtius reaction are also characterized by issues related to toxicity and the high boiling point of DPPA, which creates difficulties during workup and purification. Other general methods for carbamate preparation involve the use of the highly toxic phosgene,61 phosgene derivatives, or isocyanates. (J Med Chem. 2015 Apr 9; 58(7): 2895–2940.)
Resveratrol (3, 5, 4′-trihydroxy-trans-stilbene), a plant polyphenol, has important drug-like properties, but its pharmacological exploitation in vivo is hindered by its rapid transformation via phase II conjugative metabolism. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, stability and in vivo pharmacokinetic behaviour of prodrugs of resveratrol in which the OH groups are engaged in an N-monosubstituted carbamate ester (-OC(O)NHR) linkage with a natural amino acid (Leu, Ile, Phe, Thr) to prevent conjugation and modulate the physicochemical properties of the molecule. We also report a convenient, high-yield protocol to obtain derivatives of this type. The new carbamate ester derivatives are stable at pH 1, while they undergo slow hydrolysis at physiological pH and hydrolyse with kinetics suitable for use in prodrugs in whole blood. After administration to rats by oral gavage the isoleucine-containing prodrug was significantly absorbed, and was present in the bloodstream as non-metabolized unaltered or partially deprotected species, demonstrating effective shielding from first-pass metabolism. We conclude that prodrugs based on the N-monosubstituted carbamate ester bond have the appropriate stability profile for the systemic delivery of phenolic compounds.
All compounds turned out to be highly stable at pH values close to that of the human stomach, no reaction occurring over 24 hours at 37 °C in 0.1 N HCl, and they underwent slow hydrolysis at near-neutral pH (pH 6.8, representing intestinal pH) thus ensuring protection of the phenolic moieties from first pass metabolism during absorption in the gastrointestinal tract. In contrast all the synthesized prodrugs hydrolyzed in murine whole blood, with kinetics suitable for use as prodrugs. (Sci Rep. 2015 Oct 14;5:15216. )
Tetrahydrocurcumin (THC), the hydrogenated and stable form of curcumin, exhibits physiological and pharmacological activities similar to curcumin. A protocol has been developed for the synthesis of novel conjugates of THC with alanine (2a), isoleucine (2b), proline (2c), valine (2d), phenylalanine (2e), glycine (2f) and leucine (2g) in high yields (43–82%). All the derivatives of THC exhibited more potent anti-microbial activity than THC against Bacillus cereus, Staphylococcus aureus, Escherichia coli and Yersinia enterocolitica. The MIC values of the derivatives were 24–37% of those for THC in case of both Gram-positive and Gram-negative bacteria. Derivatives 2g and 2d exhibited maximum anti-mutagenicity against Salmonella typhimurium TA 98 and TA 1538, respectively at a low concentration of 313 μg/plate, with comparable activity for THC evident only at 3750 μg/plate. These results clearly demonstrated that the conjugation of THC at the phenolic position with amino acids led to significant improvement of its in vitro biological attributes.(Food Chem. 2013 Aug 15;139(1-4):332-8.)