HIV-1 Protease Inhibitors Based on Acyclic Carbohydrates

Zuccarello, Guido; Bouzide, Abderrahim; Kvarnström, Ingemar; Niklasson, Gunilla; Svensson, S.; Brisander, Magnus; Danielson, Helena; Nillroth, Ulrika; Karlén, Anders; Hallberg, Anders; Classon, Björn; Samuelsson, Bertil

doi:10.1021/jo971562c

Cited by 42 publications

(23 citation statements)

References 36 publications

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“…D-mannitol (11). The sugar diacid 9, to the best of our knowledge, was reported for the first time by us along with the synthesis of the first sugar diacid based peptidomimetic 1.…”

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confidence: 90%

2,5-Anhydro sugar diacid and 2,5-anhydro sugar diamine based C2 symmetric peptidomimetics as potential HIV-1 protease inhibitors

Chakraborty

Ghosh

Rao

et al. 2000

Tetrahedron Letters

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Conformationally constrained molecular frameworks of the 2,5-anhydro sugar diacid (9) and 2,5anhydro sugar diamines (10, 11) were used to construct architecturally beautiful novel C 2 symmetric peptidomimetics 1-8. Although none of these compounds showed any significant HIV-1 protease inhibitory activity, further refinements in design may lead to protease inhibitors based on these rigid carbohydrate-derived scaffolds. Among the several specific targets in the cell cycle of the human immunodeficiency virus (HIV), the virally encoded homodimeric HIV-1 protease, which is an aspartyl protease required for maturation of the infectious virion, has emerged as a promising target leading to the design and evaluation of a vast array of compounds with diverse structural motifs as possible inhibitors, some of which have already been approved for the treatment of AIDS. 1-6 We describe herein the development of a new class of compounds 1-8 as potential HIV-1 protease inhibitors that are based on carbohydrate-peptide hybrid structures. In this approach, identical peptide chains are anchored on both sides of a core carbohydrate motifa C 2 symmetric 2,5-anhydro sugar diacid or sugar diamine-leading to the formation of C 2 symmetric peptidomimetics. 7 Carbohydrate-based molecular designs are increasingly drawing chemists' attention. 8,9 Detailed studies on the development of new HIV-1 protease inhibitors based on acyclic carbohydrates have recently been reported. 10-12 It is also being increasingly felt that small molecule protease inhibitors need to have restricted degrees of freedom. The success of cyclic urea based inhibitors supports this feeling. 13,14 This has prompted us to look for cyclic carbohydrate based core foundations as conformationally rigid scaffolds to build a new class of molecular frameworks as potential protease inhibitors. Two different types of cyclic carbohydrate framework-sugar diacid and sugar diamine-are employed in our designs. These molecules are 2,5-anhydro-D-idaric acid (9), 1,6diamino-2,5-anhydro-1,6-dideoxy-D-iditol (10) and 1,6-diamino-2,5-anhydro-1,6-dideoxy-Correspondence to: T. K. Chakraborty.

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“…D-mannitol (11). The sugar diacid 9, to the best of our knowledge, was reported for the first time by us along with the synthesis of the first sugar diacid based peptidomimetic 1.…”

mentioning

confidence: 90%

2,5-Anhydro sugar diacid and 2,5-anhydro sugar diamine based C2 symmetric peptidomimetics as potential HIV-1 protease inhibitors

Chakraborty

Ghosh

Rao

et al. 2000

Tetrahedron Letters

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“…We are engaged in a program where derivatized carbohydrates are employed as C 2 -symmetric HIV-1 protease inhibitors . Application of the concept of C-terminal duplication combined with suitable selection of the P2/P2‘ substituents provided previously a series of potent protease inhibitors with P1/P1‘ benzyloxy groups, e.g.…”

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confidence: 99%

Design and Fast Synthesis of C-Terminal Duplicated PotentC₂-Symmetric P1/P1‘-Modified HIV-1 Protease Inhibitors

et al. 1999

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An analysis of the X-ray structure of a complex of HIV-1 protease with a linear C(2)-symmetric C-terminal duplicated inhibitor guided the selection of a series of diverse target compounds. These were synthesized with the objective to identify suitable P1/P1' substituents to provide inhibitors with improved antiviral activity. Groups with various physical properties were attached to the para-positions of the P1/P1' benzyloxy groups in the parent inhibitor. A p-bromobenzyloxy compound, prepared in only three steps from commercially available starting materials, was utilized as a common precursor in all reactions. The subsequent coupling reactions were completed within a few minutes and relied on palladium catalysis and flash heating with microwave irradiation. All of the compounds synthesized exhibited good inhibitory potency in the protease assay, with K(i) values ranging from 0.09 to 3.8 nM. A 30-fold improvement of the antiviral effect in cell culture, compared to the parent compound, was achieved with four of the inhibitors. The differences in K(i) values were not correlated to the differences in antiviral effect, efficiency against mutant virus, or reduced potency in the presence of human serum. The poorest enzyme inhibitors in fact belong to the group with the best antiviral effect. The binding features of two structurally related inhibitors, cocrystallized with HIV-1 protease, are discussed with special emphasis on the interaction at the enzyme/water phase.

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“…The benzoate ester was cleaved using NaOMe in MeOH to give the inverted alcohol 11a in 68% yield. Mitsunobu conditions, utilizing DPPA [ 14 ], generated the azide 12a with inversion of configuration in 98% yield. The acetal in 12a was hydrolyzed in AcOH (aq.)…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors

Sandgren

Belda

Kvarnström

et al. 2015

TOMCJ

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A series of arylketo-containing P1-P3 linked macrocyclic BACE-1 inhibitors were designed, synthesized, and compared with compounds with a previously known and extensively studied corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme- and cell-based activities. Several inhibitors displayed substantial increases in Caco-2 cell-based permeability compared to earlier synthesized inhibitors and notably also with retained activities, showing that this approach might yield BACE-1 inhibitors with improved properties.

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HIV-1 Protease Inhibitors Based on Acyclic Carbohydrates

Abstract: A series of acyclic C 2-symmetric HIV protease inhibitors readily accessible from d-mannitol have been developed. Several of the compounds synthesized showed significant in vitro activity against HIV-1 protease.

Cited by 42 publications

References 36 publications

2,5-Anhydro sugar diacid and 2,5-anhydro sugar diamine based C2 symmetric peptidomimetics as potential HIV-1 protease inhibitors

2,5-Anhydro sugar diacid and 2,5-anhydro sugar diamine based C2 symmetric peptidomimetics as potential HIV-1 protease inhibitors

Design and Fast Synthesis of C-Terminal Duplicated PotentC₂-Symmetric P1/P1‘-Modified HIV-1 Protease Inhibitors

Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors

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HIV-1 Protease Inhibitors Based on Acyclic Carbohydrates

Abstract: A series of acyclic C 2-symmetric HIV protease inhibitors readily accessible from d-mannitol have been developed. Several of the compounds synthesized showed significant in vitro activity against HIV-1 protease.

Cited by 42 publications

References 36 publications

2,5-Anhydro sugar diacid and 2,5-anhydro sugar diamine based C2 symmetric peptidomimetics as potential HIV-1 protease inhibitors

2,5-Anhydro sugar diacid and 2,5-anhydro sugar diamine based C2 symmetric peptidomimetics as potential HIV-1 protease inhibitors

Design and Fast Synthesis of C-Terminal Duplicated PotentC2-Symmetric P1/P1‘-Modified HIV-1 Protease Inhibitors

Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors

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Design and Fast Synthesis of C-Terminal Duplicated PotentC₂-Symmetric P1/P1‘-Modified HIV-1 Protease Inhibitors