10389-65-8Relevant articles and documents
Novel amphiphilic PEG-hydroxycamptothecin conjugates as glutathione-responsive prodrug nanocapsules for cancer chemotherapy
Guo, Na,Hao, Tiantian,Shang, Xiuzhuan,Zhang, Tianle,Liu, Huan,Zhang, Qian,Wang, Jing,Jiang, Du,Rong, Yao,Teng, Yuou,Yu, Peng
, (2017)
A series of novel hydroxycamptothecin (HCPT) conjugates (13a–14d), which contained a polyethylene glycol moiety and disulfide bond, were designed and synthesized in five to six steps, with overall yields of 20–39%. The anticancer activities and toxicities of these new conjugates were evaluated using an in vitro MTT assay in K562, HepG2, and HT-29 cell lines and HUVECs. The conjugates displayed enhanced antitumor activity and reduced toxicity in comparison with their parent molecule, HCPT. Among these conjugates, compound 13a exhibited 100-fold better selectivity to the tumor cells than to HUVECs. TEM and DLS experiments demonstrated that 13a formed nanosized micelles with a diameter of approximately 200?nm in aqueous solution and that the conjugate could undergo glutathione-responsive degradation to release HCPT at the tumor site. The improved potency and reduced toxicity of these conjugates may be caused by the enhanced permeation and retention (EPR) effect of nanoparticles.
Design and development of stable, water-soluble, human toll-like receptor 2 specific monoacyl lipopeptides as candidate vaccine adjuvants
Salunke, Deepak B.,Connelly, Seth W.,Shukla, Nikunj M.,Hermanson, Alec R.,Fox, Lauren M.,David, Sunil A.
, p. 5885 - 5900 (2013)
Antigens in modern subunit vaccines are largely soluble and poorly immunogenic proteins inducing relatively short-lived immune responses. Appropriate adjuvants initiate early innate immune responses, amplifying subsequent adaptive immune responses. Agonists of Toll-like receptor 2 (TLR2) are devoid of significant proinflammatory activity in ex vivo human blood models and yet are potently adjuvantic, suggesting that this chemotype may be a safe and effective adjuvant. Our earlier work on the monoacyl lipopeptide class of TLR2 agonists led to the design of a highly potent lead but with negligible aqueous solubility, necessitating the reintroduction of aqueous solubility. We explored several strategies of introducing ionizable groups on the lipopeptide, as well as the systematic evaluation of chemically stable bioisosteres of the ester-linked palmitoyl group. These studies have led to a fully optimized, chemically stable, and highly water-soluble human TLR2-specific agonist, which was found to have an excellent safety profile and displayed prominent adjuvantic activities in rabbit models.
Zinc-acetic acid reductive cyclisation in a two-step synthesis of the S1-N10 nine-membered lactone core of ent-griseoviridin
Chaume, Gregory,Kuligowski, Carine,Bezzenine-Laffolee, Sophie,Ricard, Louis,Pancrazi, Ange,Ardisson, Janick
, p. 3029 - 3036 (2004)
The synthesis of the S1-N10 nine-membered lactone core 28 of enf-griseoviridin is reported. Starting from cystine derivative 25, encompassing a terminal ynoate, treatment under Zn/AcOH conditions led to the formation of lactone 28 in 12% yield. Therefore, the lactone moiety of enf-griseoviridin is obtained in 10.7% overall yield for two steps. An access to the corresponding 5-epi-griseoviridin lactone 29 is also described.
Gd-DTPA L-cystine bisamide copolymers as novel biodegradable macromolecular contrast agents for MR blood pool imaging
Kaneshiro, Todd L.,Ke, Tianyi,Jeong, Eun-Kee,Parker, Dennis L.,Lu, Zheng-Rong
, p. 1285 - 1294 (2006)
Purpose. The purpose of this study was to synthesize biodegradable Gd-DTPA l-cystine bisamide copolymers (GCAC) as safe and effective, macromolecular contrast agents for magnetic resonance imaging (MRI) and to evaluate their biodegradability and efficacy in MR blood pool imaging in an animal model. Methods. Three new biodegradable GCAC with different substituents at the cystine bisamide [R = H (GCAC), CH2CH2CH3 (Gd-DTPA l-cystine bispropyl amide copolymers, GCPC), and CH(CH3)2 (Gd-DTPA cystine bisisopropyl copolymers, GCIC)] were prepared by the condensation copolymerization of diethylenetriamine pentaacetic acid (DTPA) dianhydride with cystine bisamide or bisalkyl amides, followed by complexation with gadolinium triacetate. The degradability of the agents was studied in vitro by incubation in 15 μM cysteine and in vivo with Sprague-Dawley rats. The kinetics of in vivo contrast enhancement was investigated in Sprague-Dawley rats on a Siemens Trio 3 T scanner. Results. The apparent molecular weight of the polydisulfide Gd(III) chelates ranged from 22 to 25 kDa. The longitudinal (T 1) relaxivities of GCAC, GCPC, and GCIC were 4.37, 5.28, and 5.56 mM-1 s-1 at 3 T, respectively. The polymeric ligands and polymeric Gd(III) chelates readily degraded into smaller molecules in incubation with 15 μM cysteine via disulfide-thiol exchange reactions. The in vitro degradation rates of both the polymeric ligands and macromolecular Gd(III) chelates decreased as the steric effect around the disulfide bonds increased. The agents readily degraded in vivo, and the catabolic degradation products were detected in rat urine samples collected after intravenous injection. The agents showed strong contrast enhancement in the blood pool, major organs, and tissues at a dose of 0.1 mmol Gd/kg. The difference of their in vitro degradability did not significantly alter the kinetics of in vivo contrast enhancement of the agents. Conclusion. These novel GCAC are promising contrast agents for cardiovascular and tumor MRI, which are later cleaved into low molecular weight Gd(III) chelates and rapidly cleared from the body.
Structure-activity relationships in toll-like receptor 2-agonists leading to simplified monoacyl lipopeptides
Agnihotri, Geetanjali,Crall, Breanna M.,Lewis, Tyler C.,Day, Timothy P.,Balakrishna, Rajalakshmi,Warshakoon, Hemamali J.,Malladi, Subbalakshmi S.,David, Sunil A.
, p. 8148 - 8160 (2011)
Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C16) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.
Effect of disulphide loop length on mechanochemical structural stability of macromolecules
Wang, Feng,Diesendruck, Charles E.
, p. 2143 - 2146 (2020)
In Nature, numerous proteins have evolved to perform similar roles, such as mechanical energy dispersion in different tissues. These biological macromolecules obtain their function from their tertiary structure, but proteins with similar roles can be quite different from each other, making it hard to define what structural features could be mimicked in synthetic materials in order to improve their performance. Here, we introduce an important protein feature-disulphide loops-into synthetic polymers and study the role of the loop size on mechanical energy dispersion. By stressing these polymers in solution, we were able to show, experimentally, that the loop size, up to a certain level, has a significant effect on the chain mechanochemical fragmentation rate, indicating it is affecting the polymer unfolding in solution prior to mechanochemical scission of the polymer backbone. Importantly, this experimental study uses homopolymers, providing information on an individual parameter-loop size-which cannot be obtained from comparing different proteins. This research emphasises the use of tailor-designed polymer-peptide hybrids to study fundamental questions on protein tertiary structures.
Cationic gemini lipids with cyclen headgroups: Interaction with DNA and gene delivery abilities
Zhang, Yi-Mei,Liu, Yan-Hong,Zhang, Ji,Liu, Qiang,Huang, Zheng,Yu, Xiao-Qi
, p. 44261 - 44268 (2014)
A series of novel 1,4,7,10-tetraazacyclododecane (cyclen)-based gemini cationic lipids were synthesized, and l-cystine was used as backbone between the two amphiphilic units. The liposomes formed from the lipids and DOPE could efficiently condense plasmid DNA into nanoparticles with suitable size and zeta-potentials, which might be suitable for gene transfection. These lipids were applied as non-viral gene delivery vectors, and their structure-activity relationship was studied. It was found that both the hydrophobic tails and the linking group could largely influence the transfection efficiency, and the oleylamine derived lipid gave the best transfection results, which were close to the commercially available transfection reagent lipofectamine 2000. The gemini structure would favor the gene transfection, and the transfection efficiency of the gemini lipid was much higher than the mono counterpart. Besides, these lipids have very low cytotoxicity, suggesting their good biocompatibility. Results indicate that such gemini lipids might be promising non-viral gene delivery vectors. This journal is
An efficient and scalable synthesis of potent TLR2 agonistic PAM2CSK4
Kaur, Arshpreet,Poonam,Patil, Madhuri T.,Mehta, Surinder K.,Salunke, Deepak B.
, p. 9587 - 9596 (2018)
Diacylated PAM2CSK4, a highly expensive lipopeptide with desirable aqueous solubility and a broad spectrum of cytokine/chemokine induction is a most potent dual (human and murine) Toll-Like Receptor-2 (TLR2) agonist. Besides such thrilling characteristics, its synthetic process is not reported in the literature. The present report describes an efficient and scalable 20 step synthesis of PAM2CSK4 in good yield (all steps > 60%) along with a clear description of the hindrances and easy solutions adopted in each step. Overall, a convergent synthetic approach was adopted involving synthesis of appropriately protected starting materials, synthesis of a key backbone skeleton PAM2CS, synthesis of a tetralysine fragment and the final coupling to yield PAM2CSK4. Tedious column chromatography was avoided on a large scale in many steps.
t-BUTYL 2-PYRIDYL CARBONATE. A USEFUL REAGENT FOR t-BUTOXYLATION OF AMINO ACIDS
Kim, Sunggak,Lee, Jae In
, p. 237 - 238 (1984)
t-Butyl 2-pyridyl carbonate, a stable crystalline compound, is found to be very efficient in the t-butoxycarbonylation of amino acids.
The role of disulfide-bridge on the activities of H-shape gemini-like cationic lipid based siRNA delivery
Ma, Xiao-Fei,Sun, Jing,Qiu, Chong,Wu, Yi-Fan,Zheng, Yi,Yu, Min-Zhi,Pei, Xi-Wei,Wei, Lin,Niu, Yu-Jie,Pang, Wen-Hao,Yang, Zhen-Jun,Wang, Jian-Cheng,Zhang, Qiang
, p. 99 - 111 (2016)
In our previous study, a H-shape gemini-like cationic lipid (ssGLCL, formerly named as CLD), composed of two hydrophilic lysine heads and two hydrophobic oleyl alcohol tails with a bridge of the redox-active disulfide-bond, had been synthesized and used as a nanocarrier for delivering small interfering RNAs (siRNAs) into cells. In order to further elucidate the role of disulfide ( - S - S - ) bridge on the activity of ssGLCL based siRNA delivery, a comparable ccGLCL bridged with a non-reducible carbon-carbon bond was synthesized and used as control in this study. Both two H-shape GLCL molecules could individually self-assemble into cationic nanoparticles in water phase and complex with negatively-charged siRNA into nanoplexes with particle size of ~ 200 nm and zeta potential of ~ + 30 mV, and exhibit effective siRNA delivery both in vitro and in vivo. Investigation of internalization pathway displayed that both ssGLCL/siRNA and ccGLCL/siRNA nanoplexes were predominantly internalized into MCF-7 cells by the clathrin-mediated endocytosis pattern. Although a lower cellular uptake of siRNA was found in the human breast cancer MCF-7 cells, the ssGLCL/siRNA nanoplexes could exhibit similar or even stronger down-regulation effects on the targeted EGFR mRNA and protein in MCF-7 cells when compared to the ccGLCL/siRNA nanoplexes. Furthermore, mechanistic study showed that the enhanced down-regulation effects of ssGLCL/siRNA nanoplexes on targeted mRNA and protein were probably attributed to the increased release of siRNA from lysosomes to cytoplasm following the cleavage of redox-active disulfide-bridge in ssGLCL. Therefore, we believed that the redox-active H-shape ssGLCL could be a potential nanocarrier towards improving siRNA delivery.
