Method for the synthesis of pyrrole and imidazole carboxamides on a solid support
First Claim
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1. A method for preparing a polyamide containing imidazole and pyrrole carboxamide groups on a solid support comprising:
- (a) preparing a resin for attachment of the polyamide;
(b) reacting an amino acid with reagents to provide an amino acid containing an amino group which is protected and a carboxyl reactive with an amino functionality.(c) sequentially deprotecting the amino acid and adding the protected and reactive amino acids to the solid support beginning with the carboxy terminal amino acid, thereby forming the desired polyamide;
(d) cleaving the polyamide from the resin; and
(e) purifying the polyamide.
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Abstract
The present invention describes a novel method for the solid phase synthesis of polyamides containing imidazole and pyrrole carboxamides. The polyamides are prepared on a solid support from aromatic carboxylic acids and aromatic amines with high stepwise coupling yields (>99%), providing milligram quantities of highly pure polyamides. The present invention also describes the synthesis of analogs of the natural products Netropsin and Distamycin A, two antiviral antibiotics. The present invention also describes a novel method for the solid phase synthesis of imidazole and pyrrole carboxamide polyamide-oligonucleotide conjugates. This methodology will greatly increase both the complexity and quantity of minor-groove binding polyamides and minor-groove binding polyamide-oligonucleotide conjugates which can be synthesized and tested.
135 Citations
49 Claims
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1. A method for preparing a polyamide containing imidazole and pyrrole carboxamide groups on a solid support comprising:
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(a) preparing a resin for attachment of the polyamide; (b) reacting an amino acid with reagents to provide an amino acid containing an amino group which is protected and a carboxyl reactive with an amino functionality. (c) sequentially deprotecting the amino acid and adding the protected and reactive amino acids to the solid support beginning with the carboxy terminal amino acid, thereby forming the desired polyamide; (d) cleaving the polyamide from the resin; and (e) purifying the polyamide. - View Dependent Claims (2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 26, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49)
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5. A method for preparing a polyamide containing N-methyl 4-imidazolecarboxamide and N-methyl-pyrrolecarboxamide comprising:
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(a) sequentially adding amino acids with an amino group protected with tert-butoxycarbonyl or 9-fluorenylmethylcarbonyl and a carboxy group that has been reacted to form an activated ester or a symmetric anhydride to an amino substituted solid support, beginning with the carboxy terminal amino acid, thereby forming a polyamide having a protected amino acid; (b) deprotecting the amino terminal protected amino acid of the polyamide; and (c) removing the polyamide from the solid support.
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19. The method of claim l wherein the polyamide is cleaved from the resin by aminolysis with an amine selected from the group consisting of dimethylaminopropylamine (Dp), 3,3'"'"'-diamino-Nmethyldipropylamine (Ta), or ethylene-diamine (ED), and β
- -alanine(β
).
- -alanine(β
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22. A polyamide capable of forming hydrogen bonds with nucleotide bases in the minor-groove of double-stranded DNA produced by the method of claim I and wherein said polyamide contains at least seven monomer units.
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23. A method for preparing a cyclic polyamide on a solid support comprising:
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(a) preparing a resin for attachment of the polyamide; (b) reacting the resin with a protected allyl ester pyrrole monomer having the following structure;
##STR31## (c) reacting an amino acid with reagents to provide an amino group which is protected and a carboxyl reactive with an amino functionality;(d) sequentially adding the protected and reactive amino acids to the solid support beginning with the carboxy terminal amino acid, thereby forming the desired polyamide; (e) removing the allyl ester with a Pd catalyst; (f) cleaving the polyamide from the resin; and (g) cyclizing and purifying the cyclized polyamide. - View Dependent Claims (24, 25, 47)
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27. A method for preparing a polyamide containing N-methyl imidazolecarboxamide and N-methyl-pyrrolecarboxamide on a solid support comprising:
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(a) preparing an amino substituted polystyrene resin solid support for attachment of the polyamide; (b) protecting the amino group of an amino acid with a member of the group consisting of tert-butoxycarbonyl or 9-fluorenylmethylcarbonyl and reacting the carboxyl group to form the oxybenztriazole ester or a symmetric anhydride; (c) sequentially deprotecting the amino acid and adding the protected amino acids to the solid support beginning with the carboxy terminal amino acid, thereby forming the desired polyamide; (d) cleaving the polyamide from the resin by hydrogenolysis; and (e) purifying the polyamide. - View Dependent Claims (28)
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Specification
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Current AssigneeCalifornia Institute of Technology
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Original AssigneeCalifornia Institute of Technology
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InventorsDervan, Peter B., Baird, Eldon
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Primary Examiner(s)Higel, Floyd D.
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Application NumberUS08/607,078Time in Patent Office1,604 DaysField of Search548/312.4, 548/312.7, 548/313.1, 548/334.5, 548/312.1, 536/25.3, 536/22.1, 536/23.1, 536/25.33, 536/25.6, 536/26.1US Class Current548/312.4CPC Class CodesA61K 38/00 Medicinal preparations cont...A61K 47/645 Polycationic or polyanionic...C07D 207/34 with hetero atoms or with c...C07D 233/90 Carbon atoms having three b...C07D 403/14 containing three or more he...C07K 5/06139 with the first amino acid b...C07K 5/06182 and Pristinamycin II; Deriv...C07K 7/02 Linear peptides containing ...C07K 7/04 Linear peptides containing ...C08G 69/00 Macromolecular compounds ob...C12Q 1/6839 Triple helix formation or o...
