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Compounds and methods for trans-membrane delivery of molecules

A technology of compounds and conjugates, applied in the field of compounds and methods for transmembrane delivery of molecules, capable of solving problems such as heavy charged structures and large OD

Pending Publication Date: 2020-09-01
APOSENSE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Due to the large and heavy charged structure of OD, there is an unmet need for a delivery system capable of delivering OD across hydrophobic phospholipid membranes into cells

Method used

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  • Compounds and methods for trans-membrane delivery of molecules
  • Compounds and methods for trans-membrane delivery of molecules
  • Compounds and methods for trans-membrane delivery of molecules

Examples

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example 1

[0326] Example 1: General method for the synthesis of conjugates according to embodiments of the invention, wherein moiety D is an oligonucleoside acid :

[0327] First, genes to be silenced are selected based on their role in disease etiology or pathogenesis. Then, based on bioinformatics methods known in the art, the nucleotide sequence to be incorporated into the conjugate is designed and determined [usually 19-21 base pair double-stranded siRNA for RISC substrates, or for Dicer The substrate (dsiRNA) is a double-stranded RNA of 24-29 base pairs].

[0328] Synthesis proceeds in the 3' to 5' direction of the oligonucleotide. Apply solid phase synthesis using protected building blocks derived from: protected 2'-deoxynucleosides (dA, dC, dG and dT), ribonucleosides (A, C, G and U) or chemical modifications Nucleosides such as [locked nucleic acid (LNA) or bridging nucleic acid (BNA)] . The building blocks are provided as nucleoside precursors in which the 5'- and 3'-h...

example 2

[0330] Example 2: Method for Chemical Synthesis of Precursor Molecules Comprising E, E' or E" Moieties of the Invention :

example 2

[0331] Example 2A: Synthesis of key intermediate phenol 1 :

[0332]

[0333] Treatment of estradiol with excess sodium hydride followed by addition of allyl bromide resulted in complete conversion towards compound 3. Subsequent hydroboration with 1.5 equivalents of 9-BBN yielded only terminal hydroxyl groups, whereas with BH 3 The hydroboration of is much less selective and provides a mixture of adducts. Alcohol 5 was subjected to Mitsunobu reaction conditions to couple it with perfluorinated tert-butanol to give compound 6. Hydrogenolysis of the benzyl group of compound 8 affords phenol 1. In summary, phenol 1 was prepared from estradiol in 45% overall yield via 5 synthetic steps:

[0334] 2bA1.(8R,9S,13S,14S,17S)-3-benzyloxy-17-hydroxyestradiol-1,3,5(10)-triene (2):

[0335] The synthesis of (8R,9S,13S,14S,17S)-3-benzyloxy-17-hydroxyestradiol-1,3,5(10)-triene (2) is disclosed in Section 2aA1 above.

[0336] 2bA2.(8R,9S,13S,14S,17S)-17-allyloxy-3-benzyloxyestra...

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Abstract

The Invention provides a novel delivery system for delivery of drugs across biological membranes. It provides novel chemical conjugates that comprise said delivery system, methods for synthesis of said compounds, and methods for utilization of said delivery system, among others, for delivery of genetic drugs into tissues and cells, in vitro, ex vivo, and in vivo, for the treatment of various medical disorders.

Description

technical field [0001] The present invention relates to compounds and conjugates comprising delivery systems, cargo compounds and macromolecules and methods for the delivery of molecules and macromolecules across biological membranes into cells intended for in vitro and in vivo biological purposes. Background technique [0002] An "oligonucleotide drug" (OD) is a macromolecular drug comprising a sequence of nucleosides or nucleotides. OD has the potential to revolutionize medical treatment for many medical conditions. As known in the art, OD is a single or double stranded, natural or modified RNA or DNA molecule or a combination thereof. Examples of OD are inter alia siRNA (small interfering RNA), which is a substrate of the RNA-induced silencing complex (RISC); siRNA sequences (dsiRNA), microRNA (miRNA), messenger RNA as substrates for Dicer endonuclease (mRNA) drugs, or DNA sequences designed to act as antisense oligonucleotides (ASOs); all are active in the downregulati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/28A61K47/54
CPCA61K47/554C12N15/00A61K31/713C07J41/0033
Inventor 伊兰·齐夫哈吉特·格林贝格约瑟夫·杜布罗夫斯基
Owner APOSENSE
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