A tetrazine templated method for the synthesis of ternary conjugates

Rao, Boddu Venkateswara; Dhokale, Snehal; Rajamohanan, Pattuparambil R.; Hotha, Srinivas

doi:10.1039/c3cc46634e

Cited by 20 publications

(11 citation statements)

References 38 publications

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“… a Reagents and conditions: (a) 3-bromopropanol, BF 3 –OEt 2 , 20 h; b) (i) 2-methyl-di- tert -butyl malonate, NaH, DMF, 24 h; (ii) NaOMe, MeOH, 2 h; (c) TFA, DCM, 5 h; (d) (i) 3-bromopropanol, BF 3 –OEt 2 , 20 h, (ii) anhydrous FeCl 3 , DCM, 36 h; (e) (i) (DACH)PtCl 2 , Ag 2 SO 4 , H 2 O, 20 h, (ii) Ba(OH) 2 , H 2 O, 24 h. , …”

Section: Resultsmentioning

confidence: 99%

Chemical Approach to Positional Isomers of Glucose–Platinum Conjugates Reveals Specific Cancer Targeting through Glucose-Transporter-Mediated Uptake in Vitro and in Vivo

2016

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Glycoconjugation is a promising strategy for specific targeting of cancer. In this study, we investigated the effect of D-glucose substitution position on the biological activity of glucose-platinum conjugates (Glc-Pts). We synthesized and characterized all possible positional isomers (C1α, C1β, C2, C3, C4 and C6) of a Glc-Pt. The synthetic routes presented here could in principle be extended to prepare glucose-conjugates with different active ingredients than platinum. The biological activities of the compounds were evaluated both in vitro and in vivo. We discovered that variation in position of substitution of D-glucose not only alters the cellular uptake and cytotoxicity profile but also the GLUT1 specificity of resulting glycoconjugates, where GLUT1 is glucose transporter 1. The C1α- and C2-substituted Glc-Pts (1α and 2) accumulate in cancer cells most efficiently compared to the others, whereas the C3-Glc-Pt (3) is taken up least efficiently. Compounds 1α and 2 are more potent compared to 3 in DU145 cells. The α- and β-anomer of the C1-Glc-Pt also differ significantly in their cellular uptake and activity profiles. No significant differences in uptake of the Glc-Pts were observed in noncancerous RWPE2 cells. The GLUT1 specificity of the Glc-Pts was evaluated by determining the cellular uptake in the absence and presence of the GLUT1 inhibitor cytochalasin B, and by comparing their anticancer activity in DU145 cells and a GLUT1 knockdown cell line. The results reveal that C2-substituted Glc-Pt 2 has the highest GLUT1 specific internalization, which also reflects the best cancer targeting ability. In a syngeneic breast cancer mouse model overexpressing GLUT1, compound 2 showed antitumor efficacy and selective uptake in tumors with no observable toxicity. This study thus reveals the synthesis of all positional isomers of D-glucose substitution for platinum warhead with detailed glycotargeting characterization in cancer.

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Section: Resultsmentioning

confidence: 99%

Chemical Approach to Positional Isomers of Glucose–Platinum Conjugates Reveals Specific Cancer Targeting through Glucose-Transporter-Mediated Uptake in Vitro and in Vivo

2016

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“…The two enantiomers N -methyl- l -cysteine and N -methyl- d -cysteine, which are required in the final step of PCH and enantio-PCH chemical synthesis, were prepared according to literature procedures, , starting from commercially available l - or d -cysteine. In this synthetic procedure (Figure S1), cysteine enantiomers were separately reacted with trityl alcohol in TFA to protect the thiol group as S -trytil, and then the amine group was protected as tert -butoxycarbonyl (Boc) carbamate that, after N -methylation with methyl iodide, gave the fully protected S -trityl, N -Boc, N -methyl l - or d -cysteine.…”

Section: Methodsmentioning

confidence: 99%

A Highly Sensitive Luminescent Biosensor for the Microvolumetric Detection of thePseudomonas aeruginosaSiderophore Pyochelin

et al. 2021

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The pyochelin (PCH) siderophore produced by the pathogenic bacterium Pseudomonas aeruginosa is an important virulence factor, acting as a growth promoter during infection. While strong evidence exists for PCH production in vivo , PCH quantification in biological samples is problematic due to analytical complexity, requiring extraction from large volumes and time-consuming purification steps. Here, the construction of a bioluminescent whole cell-based biosensor, which allows rapid, sensitive, and single-step PCH quantification in biological samples, is reported. The biosensor was engineered by fusing the promoter of the PCH biosynthetic gene pchE to the luxCDABE operon, and the resulting construct was inserted into the chromosome of the Δ pvdA Δ pchD Δ fpvA siderophore-null P. aeruginosa mutant. A bioassay was setup in a 96-well microplate format, enabling the contemporary screening of several samples in a few hours. A linear response was observed for up to 40 nM PCH, with a lower detection limit of 1.64 ± 0.26 nM PCH. Different parameters were considered to calibrate the biosensor, and a detailed step-by-step operation protocol, including troubleshooting specific problems that can arise during sample preparation, was established to achieve rapid, sensitive, and specific PCH quantification in both P. aeruginosa culture supernatants and biological samples. The biosensor was implemented as a screening tool to detect PCH-producing P. aeruginosa strains on a solid medium.

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“…Glc-EG n primers were synthesized by adopting previously reported methodologies. 49 Briefly, a mixture of O-pentaaceyl-β-D-glucoside (1 equiv), oligo-(ethylene glycol) monomethyl ether (1.2 equiv), and pulverized activated MS-4A in dry DCM was stirred at ambient temperature under argon atmosphere to remove any trace amount of water. The reaction solution was cooled to 0 °C and boron trifluoride diethyl etherate (5 equiv) was added portion-wise to the reaction solution.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Enzymatic Synthesis of Oligo(ethylene glycol)-Bearing Cellulose Oligomers for in Situ Formation of Hydrogels with Crystalline Nanoribbon Network Structures

et al. 2016

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Enzymatic synthesis of cellulose and its derivatives has gained considerable attention for use in the production of artificial crystalline nanocelluloses with unique structural and functional properties. However, the poor colloidal stability of the nanocelluloses during enzymatic synthesis in aqueous solutions limits their crystallization-based self-assembly to greater architectures. In this study, oligo(ethylene glycol) (OEG)-bearing cellulose oligomers with different OEG chain lengths were systematically synthesized via cellodextrin phosphorylase-catalyzed oligomerization of α-d-glucose l-phosphate monomers against OEG-bearing β-d-glucose primers. The products were self-assembled into extremely well-grown crystalline nanoribbon network structures with the cellulose II allomorph, potentially due to OEG-derived colloidal stability of the nanoribbon's precursors, followed by the in situ formation of physically cross-linked hydrogels. The monomer conversions, average degree of polymerization, and morphologies of the nanoribbons changed significantly, depending on the OEG chain length. Taken together, our findings open a new avenue for the enzymatic reaction-based facile production of novel cellulosic soft materials with regular nanostructures.

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A tetrazine templated method for the synthesis of ternary conjugates

Cited by 20 publications

References 38 publications

Chemical Approach to Positional Isomers of Glucose–Platinum Conjugates Reveals Specific Cancer Targeting through Glucose-Transporter-Mediated Uptake in Vitro and in Vivo

Chemical Approach to Positional Isomers of Glucose–Platinum Conjugates Reveals Specific Cancer Targeting through Glucose-Transporter-Mediated Uptake in Vitro and in Vivo

A Highly Sensitive Luminescent Biosensor for the Microvolumetric Detection of thePseudomonas aeruginosaSiderophore Pyochelin

Enzymatic Synthesis of Oligo(ethylene glycol)-Bearing Cellulose Oligomers for in Situ Formation of Hydrogels with Crystalline Nanoribbon Network Structures

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