Methods of making epothilones
Inventors
Carney, John R. • Li, Yong • Menzella, Hugo • Reid, Ralph C.
Assignees
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Publication Number
US-7955824-B2
Publication Date
2011-06-07
Expiration Date
Abstract
The invention provides novel compounds that may be used as intermediates in the preparation of epothilones, epothilone analogs and derivative, as well as new synthetic methods for producing the intermediates and products.
Core Innovation
The invention relates to preparing epothilone compounds and epothilone intermediates by combining chemical synthesis of thioester intermediates with fermentation or biotransformation using engineered host cells that express recombinant polyketide synthase systems. A thioester of formula (I) is converted by a polyketide synthase into a compound of formula (II), and the described approach includes using an engineered polyketide synthase architecture to biosynthetically extend a formula (I) thioester by 2-carbon units to reach formula (II).
The document describes epothilone and analog context, including epothilone B, ixabepilone (BMS-247550), EPO-ZK, desoxyepothilone B (epothilone D), trans-9,10-dehydroepothilone D, and 26-trifluoro trans-9,10-dehydroepothilothone D (fludelone). The background motivates the need for more efficient manufacturing of epothilone intermediates and epothilone analogs, and the pathway includes a formula (I) thioester extended to a named formula (II) compound (Compound 1).
Polyketide synthase architectures are described in terms of modular or bimodular domain arrangements, including modules and domains such as thioesterase (TE), acyltransferase (AT), acyl carrier protein (ACP), beta-ketoacyl synthase (KS), ketoreductase (KR), dehydratase (DH), and enoylreductase (ER), together with domain linkers. Engineered systems include two extension modules plus a thioesterase to drive conversion of the input thioester into the target tetraketide intermediate, followed by subsequent chemical conversion toward epothilone analogs.
Claims Coverage
The document provides two independent claims that cover a method of preparing a formula (II) compound by polyketide synthase conversion of a formula (I) thioester in a host cell, and an isolated formula (I) compound defined by substituents R1 and R4.
Host-cell polyketide synthase conversion of a formula (I) thioester to formula (II)
Growing a host cell comprising a polyketide synthase in a medium comprising a thioester of formula (I) under conditions wherein the polyketide synthase converts the thioester of formula (I) into the compound of formula (II).
Isolated compound of formula (I)
An isolated compound of formula (I) wherein R1 is H, unsubstituted lower alkyl, or substituted lower alkyl, and R4 is linear C1-C10 alkyl, or CH2CH2NH(CO)R5, wherein R5 is C1-C10 alkyl.
Claim coverage centers on enzymatic conversion of a chemically prepared formula (I) thioester to a formula (II) product in a host cell expressing a polyketide synthase, and structural definition of an isolated formula (I) thioester compound within the scope of R1 and R4 substituents.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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