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Minimal saponin analogues, synthesis and use thereof

A technology of drugs and compounds, applied in the field of adjuvants derived from triterpene glycosides and saponins, which can solve problems such as limited access to natural sources, hindering the rational development of analogues, and instability

Active Publication Date: 2017-04-19
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although promising, QS-21 also has some disadvantages, including limited access to its natural sources, toxic side effects, and chemical instability due to spontaneous hydrolysis of the acyl chain
Furthermore, poor understanding of its molecular mechanism of action hinders the rational development of analogs with improved potency and reduced toxicity

Method used

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  • Minimal saponin analogues, synthesis and use thereof
  • Minimal saponin analogues, synthesis and use thereof
  • Minimal saponin analogues, synthesis and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0172] Example 1: Preliminary evaluation of iodinated saponins 6 and 8

[0173] Radioactive iodine ( 131 I) Introduced into the QS-21 saponin backbone to achieve biodistribution studies in vivo. Synthesis of non-radiolabeled aryl iodide 6 (SQS-0-0-5-18) via acylation of amine 2 (SQS-0-0-5-11) ( Figure 1b ). Because no in vitro model exists to assess adjuvant activity, the biological evaluation of aryl iodide 6 was performed in a preclinical mouse vaccination model involving a multi-antigen formulation comprising the immunogenic peptide MUC1 (prostate and Breast cancer antigen, aglycosylated tandem repeat), which is conjugated to a highly immunogenic KLH carrier protein (MUC1-KLH) and OVA, a reliable immunogen that induces antibody and T cell responses in mice. Antibody responses to each of the three antigens co-administered with the adjuvants of interest were determined by ELISA.

[0174] Antibody titers induced by aryl iodide saponin 6 (SQS-0-0-5-18) were comparable to N...

Embodiment 2

[0176] Embodiment 2: radioactive iodinated saponins [ 131 I] -6 and[ 131 I] -8 Biodistribution of

[0177] For biodistribution studies, radiolabeled aryl iodide saponins were synthesized by aryl tin-halide exchange of trimethylstannane 7[ 131 I] -6 ([ 131 I]-SQS-0-0-5-18)( Figure 1b ). Radioiodinated [ 131 I] -8 ([ 131 I]-SQS-0-3-7-18) as a negative control ( Figure 1c ).

[0178] To identify tissues and organs capable of playing a role in the saponin mechanism of action, the active adjuvant [ 131 I] -6 The acute in vivo biodistribution and attenuated adjuvant in mice co-administered with OVA[ 131 I] -8 Compare. and[ 131 I] -8 Compared with [ 131 I] -6 Treatment resulted in ( Figure 2a ) significantly higher recovery of radioactivity, which was retained at 72 and 96 hours post-injection (Figure 8). Conversely, radioactivity in other tissues where large fold differences were initially observed (muscle, bone, skin) decreased rapidly at later time points....

Embodiment 3

[0183] Example 3: Truncated saponins lacking branched trisaccharide domains (16)

[0184] The essential triterpene core is selectively silylated at the hydroxyl group (TESOTf, 2,6-lutidine) to provide the protected triterpene with free C28-carboxylic acid. β-selective Schmidt glycosylation reaction with trisaccharide trichloroacetimide donor 12 (BF 3 ·OEt 2 ) (Chea, E.K. et al. Synthesis and preclinical evaluation of QS-21 variants leading to simplified vaccine adjuvants and mechanistic probes. J. Am. Chem. Soc. 134, 13448-13457 (2012)), followed by reduction of azide (PhSeH), The corresponding glucosyl esters are obtained. The amine and 6-((tert-butoxycarbonyl)-amino)caproic acid (14) (EtOCOCl, Et 3 N) acylation reaction, and subsequent hydrogenolysis (H 2 , Pd / C) and acid hydrolysis (TFA / H 2 O) Global deprotection, resulting in a fully deprotected saponin with a free amine at the end of the acyl chain domain. Late acylation of this amine with succinimidyl esters 4 or 5...

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Abstract

Truncated triterpene saponin analogues containing a trisaccharide or tetrasaccharide ester are disclosed. Also disclosed are pharmaceutical compositions comprising truncated saponin analogues and synthetic methods of producing the truncated saponin analogues. Another aspect of the present application relates to a method for immunizing a subject, comprising administering to the subject the pharmaceutical composition comprising a minimal saponin analogue and an antigen.

Description

[0001] Cross References to Prior Applications [0002] This application claims priority to US Provisional Application No. 62 / 005,302, filed May 30, 2014. technical field [0003] The present disclosure generally relates to triterpene glycoside saponin derived adjuvants, their synthesis and their intermediates. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compounds or compositions in the treatment of infectious diseases and cancer. Background technique [0004] The clinical success of anticancer and antimicrobial vaccines critically depends on the identification and availability of novel and effective adjuvants with attenuated toxicity. Molecular vaccines composed of subunit antigens are often less immunogenic than whole pathogens and do not induce sufficient immune responses alone, requiring the inclusion of immune adjuvants to increase immunogenicity. Unfortunately, few adjuvants are sufficientl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H13/08A61K31/7024C07H15/24
CPCA61K31/7024A61K39/39A61K2039/55577C07H15/256A61P31/00A61P35/00A61K2300/00A61K31/704A61K45/06C07H15/18C07H15/24
Inventor 戴维·金埃里克·K·谢阿尔伯托·费尔南德斯-泰加达德里克·S·坦杰森·S·刘易斯杰弗里·R·加德纳尔纳加弗拉基斯·派拉瑞斯提
Owner SLOAN KETTERING INST FOR CANCER RES
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