- Synthesis and immunostimulatory activity of sugar-conjugated TLR7 ligands
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Toll-like receptors (TLRs) are a type of pattern recognition receptors (PRRs), which are activated by recognizing pathogen-associated molecular patterns (PAMPs). The activation of TLRs initiates innate immune responses and subsequently leads to adaptive immune responses. TLR agonists are effective immuomodulators in vaccine adjuvants for infectious diseases and cancer immunotherapy. In exploring hydrophilic small molecules of TLR7 ligands using the cell-targeted property of a vaccine adjuvant, we conjugated 1V209, a small TLR7 ligand molecule, with various low or middle molecular weight sugar molecules that work as carriers. The sugar-conjugated 1V209 derivatives showed increased water solubility and higher immunostimulatory activity in both mouse and human cells compared to unmodified 1V209. The improved immunostimulatory potency of sugar-conjugates was attenuated by an inhibitor of endocytic process, cytochalasin D, suggesting that conjugation of sugar moieties may enhance the uptake of TLR7 ligand into the endosomal compartment. Collectively our results support that sugar-conjugated TLR7 ligands are applicable to novel drugs for cancer and vaccine therapy.
- Baba, Akihito,Wakao, Masahiro,Shinchi, Hiroyuki,Chan, Michael,Hayashi, Tomoko,Yao, Shiyin,Cottam, Howard B.,Carson, Dennis A.,Suda, Yasuo
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supporting information
(2019/12/27)
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- Combretastatin A4-β-Galactosyl Conjugates for Ovarian Cancer Prodrug Monotherapy
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Chemotherapy for ovarian cancer often causes severe side effects. As candidates for combretastatin A4 (CA4) prodrug for ovarian cancer prodrug monotherapy (PMT), we designed and synthesized two β-galactose-conjugated CA4s (CA4-βGals), CA4-βGal-1 and CA4-βGal-2. CA4 was liberated from CA4-βGals by β-galactosidase, an enzyme more strongly expressed in ovarian cancer cells than normal cells. CA4-βGal-2, which has a self-immolative benzyl linker between CA4 and the β-galactose moiety, was more cytotoxic to ovarian cancer cell lines than CA4-βGal-1 without a linker. Therefore, CA4-βGal-2 can serve as a platform for the design and manufacture of prodrugs for ovarian cancer PMT.
- Doura, Tomohiro,Takahashi, Kazuaki,Ogra, Yasumitsu,Suzuki, Noriyuki
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supporting information
p. 211 - 214
(2017/03/08)
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- Synthesis of glycosylamines: Identification and quantification of side products
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The synthesis of some glycosylamines (1-amino-1-deoxy-D-glucose, 1-amino-1-deoxy- D-galactose and 1-amino-1-deoxylactose) was carried out by treatment of the corresponding reducing sugars with ammonium hydrogencarbonate in concentrated ammonia. The reaction mixture was first analyzed by capillary electrophoresis with indirect absorbance detection and high performance anion-exchange chromatography with pulsed amperometric detection. Beside glycosylcarbamate, a known reaction by-product, fructose and lactulose were detected during the synthesis of 1-amino-1-deoxyglucose and 1-amino-1-deoxylactose, respectively. Quantification of glycosylamines was carried out by micellar electrokinetic chromatography with UV detection of their 9-fluorenylmethyloxycarbonyl (Fmoc) derivatives; lactulosylamine was thus detected in the synthesis mixture of 1-amino-1-deoxylactose. The Fmoc-glycosylamines were easily purified from the other components of the crude synthesis mixtures.
- Campa, Cristiana,Donati, Ivan,Vetere, Amedeo,Gamini, Amelia,Paoletti, Sergio
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p. 263 - 273
(2007/10/03)
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- Platinum complexes of polyhydroxylated alkylamines and 2-polyhydroxylated alkyl-1,2-diaminoethanes
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Platinum complexes of polyhydroxylated alkylamines and 2-polyhydroxylated alkyl-1,2-diaminoethanes useful for inducing regression and/or palliation of cancer diseases in mammals.
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