Lipid A-Type Pyrancarboxylic Acid Derivatives, their Synthesis and their Biological Activities

Mochizuki, Takashi; Iwano, Yuji; Shiozaki, Masao; Kurakata, Shinichi; Kanai, Saori; Nishijima, Masahiro

doi:10.1016/s0040-4020(00)00684-0

Cited by 13 publications

(7 citation statements)

References 15 publications

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“…In this regard, many lipid A and MPLA derivatives have been prepared and evaluated in the literature. 13,14,17,[20][21][22][23][24][25][26][27][28][29][30][31] In association with our efforts to develop fully synthetic carbohydrate-based cancer vaccines, we synthesized a monophosphoryl analog 32 of N. meningitidis lipid A and coupled it to N-phenylacetyl GM3, a modified form of TACA. 33 The resulting conjugate alone induced promising immune responses in animals in the absence of any external adjuvant, suggesting that, as an immunostimulant, MPLA was functional not only as a vaccine carrier but also as a built-in adjuvant.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of monophosphoryl lipid A derivatives as fully synthetic self-adjuvanting glycoconjugate cancer vaccine carriers

et al. 2014

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Fully synthetic carbohydrate-based cancer vaccine is an attractive concept, while an important topic in the area is to develop proper vaccine carriers that can improve the immunogenicity and other immunological properties of tumor-associated carbohydrate antigens (TACAs). In this context, four monophosphoryl derivatives of Neisseria meningitidis lipid A were synthesized via a highly convergent and effective strategy and evaluated as vaccine carriers and adjuvants. The conjugates of these monophosphoryl lipid A (MPLA) derivatives with a modified form of the sTn antigen were found to elicit high titers of antigen-specific IgG antibodies, indicating T cell-dependent immune response, in the absence of an external adjuvant. It was concluded that MPLA’s could be utilized as potent vaccine carriers and built-in adjuvants to create fully synthetic self-adjuvanting carbohydrate-based cancer vaccines. The lipid composition and structure of MPLA were shown to have a significant influence on its immunological activity, and among the MPLA’s examined, natural N. meningitidis MPLA exhibited the most promising properties. Moreover, Titermax Gold, a conventional vaccine adjuvant, was revealed to inhibit, rather than promote, the immunological activity of MPLA conjugates, maybe via interacting with MPLA text goes here.

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Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of monophosphoryl lipid A derivatives as fully synthetic self-adjuvanting glycoconjugate cancer vaccine carriers

et al. 2014

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“…Other examples of bioisosteres of carbohydrate derivatives containing charged modifications include the installation of a carboxylate group at C-1 of lipid A to mimic the native phosphoric acid moiety [162]. Furthermore, 6-bromophosphonate analogues of glucose-6-phosphate were synthesized and demonstrated to inhibit glucose-6-phosphatase [163].…”

Section: Replacement Of Charged Substituentsmentioning

confidence: 99%

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

Hevey

2019

Biomimetics

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The aberrant presentation of carbohydrates has been linked to a number of diseases, such as cancer metastasis and immune dysregulation. These altered glycan structures represent a target for novel therapies by modulating their associated interactions with neighboring cells and molecules. Although these interactions are highly specific, native carbohydrates are characterized by very low affinities and inherently poor pharmacokinetic properties. Glycomimetic compounds, which mimic the structure and function of native glycans, have been successful in producing molecules with improved pharmacokinetic (PK) and pharmacodynamic (PD) features. Several strategies have been developed for glycomimetic design such as ligand pre-organization or reducing polar surface area. A related approach to developing glycomimetics relies on the bioisosteric replacement of carbohydrate functional groups. These changes can offer improvements to both binding affinity (e.g., reduced desolvation costs, enhanced metal chelation) and pharmacokinetic parameters (e.g., improved oral bioavailability). Several examples of bioisosteric modifications to carbohydrates have been reported; this review aims to consolidate them and presents different possibilities for enhancing core interactions in glycomimetics.

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“…Therefore, the total number of lipid chains in the structure of lipid A analogs was again proved to be of great importance for their LPS‐antagonistic or agonistic activity, whereas the C‐6′ substitution pattern had only a small impact on their bioactivity. These observations were in accordance with previous findings . Additionally, the 3‐tetradecanoyloxytetradecyl or 3‐dodecyloxytetradecyl group on the 3′‐ O ‐position was not critical for the inhibitory activity to human monoblastic U937 cell.…”

Section: Chemical Synthesis Of Lipid a And Its Derivativesmentioning

confidence: 99%

“…), a lipid A related monosaccharide analog with LPS‐agonistic activity, it was found that the carboxylic acid analog 73 had LPS‐antagonistic property toward human monoblastic U937 cell . Therefore, Mochizuki et al designed and synthesized a series of artificial carboxylic acid derivatives of lipid A, 74a–c and 75a–c (Fig. ), as potential LPS antagonists.…”

Section: Chemical Synthesis Of Lipid a And Its Derivativesmentioning

confidence: 99%

Progress in the synthesis and biological evaluation of lipid A and its derivatives

Gao

Guo

2017

Medicinal Research Reviews

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Lipid A is one of the core structures of bacterial lipopolysaccharides (LPSs), and it is mainly responsible for the strong immunostimulatory activities of LPS through interactions with the Toll-like receptors and other molecules in the human immune system. To obtain structurally homogeneous and well-defined lipid As and its derivatives in quantities meaningful for various biological studies and applications, their chemical synthesis has become a focal point. This review has provided a survey of significant progresses made in the synthesis of lipid A, and its derivatives that carry diverse saturated and unsaturated lipids, have the phosphate group at its reducing end replaced with a more stable phosphate or carboxyl group, or lack the reducing end phosphate or both phosphate groups, as well as progresses in the synthesis of LPS analogs and other lipid A conjugates. These synthetic molecules have facilitated the elucidation of the structure-activity relationships of lipid A useful for the design and development of lipid A based therapeutics, such as those utilized to treat sepsis, and other medical applications, for example the use of monophosphoryl lipid A as a carrier molecule for the study of fully synthetic self-adjuvanting conjugate vaccines. These topics are also briefly covered in the current review.

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Lipid A-Type Pyrancarboxylic Acid Derivatives, their Synthesis and their Biological Activities

Cited by 13 publications

References 15 publications

Synthesis and evaluation of monophosphoryl lipid A derivatives as fully synthetic self-adjuvanting glycoconjugate cancer vaccine carriers

Synthesis and evaluation of monophosphoryl lipid A derivatives as fully synthetic self-adjuvanting glycoconjugate cancer vaccine carriers

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

Progress in the synthesis and biological evaluation of lipid A and its derivatives

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