Recombined molecules and preparation thereof
a technology of recombination molecules and compounds, applied in the field of novel molecules and libraries, can solve the problems of difficult to predict which small molecules will interact with biological targets, and inability to achieve the complex structure of natural products. or other lead compounds prepared through traditional chemical synthetic routes, etc., and achieve the effect of rich stereochemical complexity
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example 1
Production of Recombined Molecule from One Starting Molecule—General Example
[0087] Chemical cleavage or enzymatic digestion of a starting molecule provides a mixture of several known fragments or molecular subunits (FIG. 1. A, B and C). The molecular subunits from this pool are evaluated for their biological properties and / or use as building blocks to generate large libraries of structurally complex products via the production of recombined molecules.
[0088] The mixture of molecular subunits is subsequently split in two pools. The subunits of each pool are blocked at a specific site by either the protection group P and protection group Q. This results in two different molecular subunit pools, which are longer able to react with themselves. Mixing of the two pools under the proper conditions results in a well defined mixture of novel protected recombined molecule products. Deprotection of the entire mixed pool with a reagent chemically, enzymetically or photochemically, provides the...
example 2
Production of Recombined Molecule from One Starting Molecule—Vancomycin
[0089] Intramolecular Recombination of Vancomycin
[0090] Cleavage of vancomycin with pepsin or other proteases provides a mixture of molecular subunits (FIG. 2). The mixture containing the molecular subunits is split in two separate pools: Pool I and Pool II. Pool I is treated with acetic anhydride or any other acylation reagents that acylate all alcohols and amino groups to yield the products shown in FIG. 3A.
[0091] Pool II is exposed to methylating conditions (TMSCHN2, AcCl / MeOH or any other chemical or enzymetic methylating procedures) for several hours. These conditions ensure methylation of all the carboxylic acid moieties present to yield the fractions shown in FIG. 3B.
[0092] Addition of the commercially available solid phase bound peptide coupling reagents (such as the carbodiimide EDCI) or any other peptide coupling reagent promote the condensation of any amine with any free (unblocked) carboxylic acid...
example 3
Production of Recombined Molecule from Two Starting Molecules—Vancomycin and Rifamycin B
[0094] Intermolecular Recombination of Vancomycin and Rifamycin B
[0095] The same methodology used for intramolecular recombination is applied to a mixture of two starting molecules. For example, the inexpensive commercially available RNA polymerase inhibitor rifamycin B (˜$50 / gram, Sigma) and vancomycin (˜$100 / gram, Sigma) is recombined intermolecularly to generate a library of high complex hybrid agents.
[0096] Cleavage of rifamycin B provides a mixture of three products with fraction 1 containing two carboxylic acids, fraction 2 one carboxylic acid and fraction 3 is oxalic acid (FIG. 4). Treatment of this mixture with the vancomycin mixture from Pool 2 (FIG. 3B) provides a library of highly complex unnatural products that can be evaluated for biological activity.
[0097] Alternatively, fraction B of Pool 2 (FIG. 3B) is isolated to simplify the out come of the reaction. Treatment of the rifamyc...
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