- Synthesis, antitumor activity and in silico analyses of amino acid derivatives of artepillin C, drupanin and baccharin from green propolis
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Breast cancer has the highest incidence and mortality in females, while prostate cancer has the second-highest incidence in males. Studies have shown that compounds from Brazilian green propolis have antitumor activities and can selectively inhibit the AKR1C3 enzyme, overexpressed in hormone-dependent prostate and breast tumors. Thus, in an attempt to develop new cytotoxic inhibitors against these cancers, three prenylated compounds, artepillin C, drupanin and baccharin, were isolated from green propolis to synthesize new derivatives via coupling reactions with different amino acids. All obtained derivatives were submitted to antiproliferative assays against four cancer cells (MCF-7, MDA MB-231, PC-3, and DU145) and two normal cell lines (MCF-10A and PNT-2) to evaluate their cytotoxicity. In general, the best activity was observed for compound 6e, derived from drupanin, which exhibited half-maximal inhibitory concentration (IC50) of 9.6 ± 3 μM and selectivity index (SI) of 5.5 against MCF-7 cells. In silico studies demonstrated that these derivatives present coherent docking interactions and binding modes against AKR1C3, which might represent a possible mechanism of inhibition in MCF-7 cells.
- Rodrigues, Débora Munhoz,Portapilla, Gisele Bulh?es,Silva, Guilherme Martins,Duarte, Andressa,Rotta, Cristiana Gon?alez,da Silva, Carlos Henrique Tomich de Paula,de Albuquerque, Sérgio,Bastos, Jairo Kenupp,Campo, Vanessa Leiria
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- Self-Adjuvanting Cancer Vaccines from Conjugation-Ready Lipid A Analogues and Synthetic Long Peptides
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Self-adjuvanting vaccines, wherein an antigenic peptide is covalently bound to an immunostimulating agent, have been shown to be promising tools for immunotherapy. Synthetic Toll-like receptor (TLR) ligands are ideal adjuvants for covalent linking to peptides or proteins. We here introduce a conjugation-ready TLR4 ligand, CRX-527, a potent powerful lipid A analogue, in the generation of novel conjugate-vaccine modalities. Effective chemistry has been developed for the synthesis of the conjugation-ready ligand as well as the connection of it to the peptide antigen. Different linker systems and connection modes to a model peptide were explored, and in vitro evaluation of the conjugates showed them to be powerful immune-activating agents, significantly more effective than the separate components. Mounting the CRX-527 ligand at the N-terminus of the model peptide antigen delivered a vaccine modality that proved to be potent in activation of dendritic cells, in facilitating antigen presentation, and in initiating specific CD8+ T-cell-mediated killing of antigen-loaded target cells in vivo. Synthetic TLR4 ligands thus show great promise in potentiating the conjugate vaccine platform for application in cancer vaccination.
- Reintjens, Niels R. M.,Tondini, Elena,De Jong, Ana R.,Meeuwenoord, Nico J.,Chiodo, Fabrizio,Peterse, Evert,Overkleeft, Herman S.,Filippov, Dmitri V.,Van Der Marel, Gijsbert A.,Ossendorp, Ferry,Codée, Jeroen D. C.
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supporting information
p. 11691 - 11706
(2020/11/26)
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- Glycosylated α-Azido Amino Acids: Versatile Intermediates in the Synthesis of Neoglycoconjugates
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A series of glycosylated α-azido amino acids was synthesized as precursors for neoglycoconjugates, a class of important biomolecules for drug discovery, and sensor development. The synthetically challenging 1,2- cis α-galactosylated species described here
- O'Flaherty, Róisín,Velasco-Torrijos, Trinidad
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supporting information
p. 904 - 907
(2018/02/16)
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- Stereoselective synthesis of natural and non-natural thomsen-nouveau antigens and hydrazide derivatives
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A selective glycosylation strategy enabling access to all stereochemical combinations of tumor associated Thomsen-nouveau (Tn) antigen, d-GalNAc-O-Ser/Thr, has been developed. The key component for selectivity is the phthalimide-protected d- or l-amino acid acceptors which allow access to α- or β-anomers in excellent yields (72-96%) and selectivity (～100%) when appropriate C-2 substitution is installed. The glycoamino acid intermediates were divergently converted to Tn-based carboxylates or to hydrazides by tandem Pd-C debenzylation followed by treatment with hydrazine hydrate or hydrazine hydrate treatment alone.
- Shaik, Ahmad Ali,Nishat, Sharmeen,Andreana, Peter R.
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p. 2582 - 2585
(2015/06/16)
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- A class of novel conjugates of substituted purine and Gly-AA-OBzl: Synthesis and evaluation of orally analgesic activity
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Aimed at the chemotherapy of chronic pain two kinds of analgesic pharmacophores, substituted purine and Gly-AA-OBzl, were coupled via a five-step-reaction procedure and 19 novel conjugates N-[2-chloro-9- (tetrahydropyran-2-yl)-9H-purin-6-yl]-N-cyclopropylglycylamino acid benzylesters were provided. On mouse-tail flick model their in vivo analgesic activities were assayed. The results indicate that introducing Gly-OC2H 5 into the 6-position of the substituted purine leads to ambiguous increase of the analgesic activity, while introducing Gly-AA-OBzl into this position leads to significant increase of the analgesic activity.
- Kang, Guifeng,Zhao, Ming,Zhang, Xiaoyi,Peng, Li,Li, Chunbo,Mao, Wei,Ye, Weidong,Peng, Shiqi
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supporting information; experimental part
p. 6157 - 6160
(2010/12/19)
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- Novel and facile solution-phase synthesis of 2,5-diketopiperazines and O-glycosylated analogs
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This work describes the synthesis in solution of a series of related diketopiperazines with potential biological activities: cyclo(l-Pro-l-Ser), cyclo(l-Phe-l-Ser), cyclo(d-Phe-l-Ser) and the corresponding glycosylated analogs of the latter, cyclo[d-Phe-l
- Campo, Vanessa L.,Martins, Maristela B.,da Silva, Carlos H.T.P.,Carvalho, Ivone
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experimental part
p. 5343 - 5349
(2009/10/17)
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- Synthesis and cytotoxic activities of β-carboline amino acid ester conjugates
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β-Carboline represents a class of compounds with potent anti-tumor activity by intercalating with DNA. To further enhance the cytotoxic potency and bioavailability of β-carboline, a series of novel β-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were tested using a panel of human tumor cell lines. In addition, the membrane permeability of these compounds was evaluated in vitro using a Caco-2 cell monolayer model. The β-carboline amino acid ester conjugates demonstrated improved cytotoxic activity compared to the parental β-carbolines. In particular, the Lys/Arg conjugates were the most potent analogs with an IC50 value of 4 and 1 μM against human cervical carcinoma cells. The low interaction energy of Arg conjugate based on molecular modeling may contribute to its enhanced cytotoxicity. Taken together, this study provided new insights into structure-activity relationships in the β-carboline amino acid ester conjugates and identified the β-carboline Lys/Arg conjugates as promising lead compounds for further in vivo biological and molecular evaluation.
- Zhao, Ming,Bi, Lanrong,Wang, Wei,Wang, Chao,Baudy-Floc'h, Michele,Ju, Jingfang,Peng, Shiqi
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p. 6998 - 7010
(2007/10/03)
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- Application of serine- and threonine-derived cyclic sulfamidates for the preparation of S-linked glycosyl amino acids in solution- and solid-phase peptide synthesis
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Cyclic sulfamidates were synthesized in 60% yield from L-serine and allo-L-threonine, respectively. These sulfamidates reacted with a variety of unprotected 1-thio sugars in aqueous bicarbonate buffer (pH 8) to afford the corresponding S-linked serine- and threonine-glycosyl amino acids with good diastereoselectivity (≥97%) after hydrolysis of the N-sulfates. The serine-derived sulfamidate was incorporated into a simple dipeptide to generate a reactive dipeptide substrate that underwent chemoselective ligation with a 1-thio sugar to afford an S-linked glycopeptide. This sulfamidate was also incorporated into a peptide on a solid support in conjunction with solid-phase peptide synthesis. Chemoselective ligation of a 1-thio sugar with the cyclic sulfamidate was achieved on the solid support, followed by removal of the N-sulfate. Finally, the peptide chain of the resulting support-bound S-linked glycopeptide was extended using standard peptide synthesis procedures.
- Cohen, Scott B.,Halcomb, Randall L.
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p. 2534 - 2543
(2007/10/03)
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