Article | Published:

Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro

Nature Chemistry volume 4, pages 705710 (2012) | Download Citation

Abstract

Bryostatin is a unique lead in the development of potentially transformative therapies for cancer, Alzheimer's disease and the eradication of HIV/AIDS. However, the clinical use of bryostatin has been hampered by its limited supply, difficulties in accessing clinically relevant derivatives, and side effects. Here, we address these problems through the step-economical syntheses of seven members of a new family of designed bryostatin analogues using a highly convergent Prins-macrocyclization strategy. We also demonstrate for the first time that such analogues effectively induce latent HIV activation in vitro with potencies similar to or better than bryostatin. Significantly, these analogues are up to 1,000-fold more potent in inducing latent HIV expression than prostratin, the current clinical candidate for latent virus induction. This study provides the first demonstration that designed, synthetically accessible bryostatin analogues could serve as superior candidates for the eradication of HIV/AIDS through induction of latent viral reservoirs in conjunction with current antiretroviral therapy.

  • Compound C42H66O12

    (1S,3S,7R,8E,11S,12S,13E,15S,17R,21R,23S)-11,21-Dihydroxy-17-(hydroxymethyl)-13-(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-5-methylene-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl octanoate

  • Compound C42H66O13

    (1S,3S,7R,8E,11S,12S,13E,15S,17R,21R,23R,25S)-11,21,25-Trihydroxy-17-(hydroxymethyl)-13-(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-5-methylene-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl octanoate

  • Compound C44H68O14

    (1S,3S,7R,8E,11S,12S,13E,15S,17R,21R,23R,25S)-25-Acetoxy-11,21-dihydroxy-17-(hydroxymethyl)-13-(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-5-methylene-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl octanoate

  • Compound C44H68O15

    (3S,7R,8E,11S,12S,13E,15S,17R,21R,23R,25S)-25-Acetoxy-1,11,21-trihydroxy-17-(hydroxymethyl)-13-(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-5-methylene-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl octanoate

  • Compound C44H68O14

    (2Z,2'E)-Dimethyl 2,2'-((1S,3S,7R,11S,12S,15S,17R,21R,23S,E)-11,21-dihydroxy-17-(hydroxymethyl)-10,10,26,26-tetramethyl-12-(octanoyloxy)-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-ene-5,13-diylidene)diacetate

  • Compound C46H70O16

    (2Z,2'E)-Dimethyl 2,2'-((1S,3S,7R,11S,12S,15S,17R,21R,23R,25S,E)-25-acetoxy-11,21-dihydroxy-17-(hydroxymethyl)-10,10,26,26-tetramethyl-12-(octanoyloxy)-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-ene-5,13-diylidene)diacetate

  • Compound C46H70O17

    (2Z,2'E)-Dimethyl 2,2'-((3S,7R,11S,12S,15S,17R,21R,23R,25S,E)-25-acetoxy-1,11,21-trihydroxy-17-(hydroxymethyl)-10,10,26,26-tetramethyl-12-(octanoyloxy)-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-ene-5,13-diylidene)diacetate

  • Compound C42H70O5Si3

    (R)-3-((tert-Butyldiphenylsilyl)oxy)-4-((2S,6S)-5,5-dimethyl-6-((S)-2-((triethylsilyl)oxy)-4-((trimethylsilyl)methyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-yl)butanoic acid

  • Compound C48H84O6Si4

    (R)-4-((2R,4S,6S)-4-((tert-Butyldimethylsilyl)oxy)-5,5-dimethyl-6-((S)-2-((triethylsilyl)oxy)-4-((trimethylsilyl)methyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-yl)-3-((tert-butyldiphenylsilyl)oxy)butanoic acid

  • Compound C45H74O8Si3

    (R)-4-((2S,4S,6S)-4-Acetoxy-6-methoxy-5,5-dimethyl-6-((S)-2-((triethylsilyl)oxy)-4-((trimethylsilyl)methyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-yl)-3-((tert-butyldiphenylsilyl)oxy)butanoic acid

  • Compound C31H54O9Si

    (2S,3S,6S,E)-6-((R)-3-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropyl)-2-hydroxy-4-(2-methoxy-2-oxoethylidene)-2-((E)-2-methyl-5-oxopent-3-en-2-yl)tetrahydro-2H-pyran-3-yl octanoate

  • Compound C34H44O5Si

    (4S,6S)-6-((S)-4-(Benzyloxy)-2-((tert-butyldiphenylsilyl)oxy)butyl)-4-hydroxy-3,3-dimethyltetrahydro-2H-pyran-2-one

  • Compound C40H56O6Si

    (R)-Ethyl 4-((2S,6S)-6-((S)-4-(benzyloxy)-2-((tert-butyldiphenylsilyl)oxy)butyl)-3,3-dimethyltetrahydro-2H-pyran-2-yl)-3-hydroxybutanoate

  • Compound C46H70O7Si2

    (R)-Ethyl 4-((2S,4S,6R)-6-((S)-4-(benzyloxy)-2-((tert-butyldiphenylsilyl)oxy)butyl)-4-((tert-butyldimethylsilyl)oxy)-3,3-dimethyltetrahydro-2H-pyran-2-yl)-3-hydroxybutanoate

  • Compound C49H78O4Si3

    (((S)-4-(Benzyloxy)-1-((2S,6S)-5,5-dimethyl-6-((S)-2-((triethylsilyl)oxy)-4-((trimethylsilyl)methyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-yl)butan-2-yl)oxy)(tert-butyl)diphenylsilane

  • Compound C55H92O5Si4

    (((S)-4-(Benzyloxy)-1-((2R,4S,6S)-4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-6-((S)-2-((triethylsilyl)oxy)-4-((trimethylsilyl)methyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-yl)butan-2-yl)oxy)(tert-butyl)diphenylsilane

  • Compound C73H122O13Si4

    (2S,3S,6S,E)-6-((R)-3-((tert-Butyldimethylsilyl)oxy)-2-(((R)-3-((tert-butyldiphenylsilyl)oxy)-4-((2S,6S)-5,5-dimethyl-6-((S)-2-((triethylsilyl)oxy)-4-((trimethylsilyl)methyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-yl)butanoyl)oxy)propyl)-2-hydroxy-4-(2-methoxy-2-oxoethylidene)-2-((E)-2-methyl-5-oxopent-3-en-2-yl)tetrahydro-2H-pyran-3-yl octanoate

  • Compound C79H136O14Si5

    (2S,3S,6S,E)-6-((R)-3-((tert-Butyldimethylsilyl)oxy)-2-(((R)-4-((2R,4S,6S)-4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-6-((S)-2-((triethylsilyl)oxy)-4-((trimethylsilyl)methyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-yl)-3-((tert-butyldiphenylsilyl)oxy)butanoyl)oxy)propyl)-2-hydroxy-4-(2-methoxy-2-oxoethylidene)-2-((E)-2-methyl-5-oxopent-3-en-2-yl)tetrahydro-2H-pyran-3-yl octanoate

  • Compound C75H124O17Si4

    (2S,3S,6S,E)-6-((R)-2-(((R)-4-((2S,4S,6S)-4-Acetoxy-6-methoxy-5,5-dimethyl-6-((S)-2-((triethylsilyl)oxy)-4-((trimethylsilyl)methyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-yl)-3-((tert-butyldiphenylsilyl)oxy)butanoyl)oxy)-3-((tert-butyldimethylsilyl)oxy)propyl)-2-hydroxy-4-(2-methoxy-2-oxoethylidene)-2-((E)-2-methyl-5-oxopent-3-en-2-yl)tetrahydro-2H-pyran-3-yl octanoate

  • Compound C64H98O12Si2

    (1S,3S,7R,8E,11S,12S,13E,15S,17R,21R,23S)-17-(((tert-Butyldimethylsilyl)oxy)methyl)-21-((tert-butyldiphenylsilyl)oxy)-11-hydroxy-13-(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-5-methylene-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl octanoate

  • Compound C70H112O13Si3

    (1S,3S,7R,8E,11S,12S,13E,15S,17R,21R,23R,25S)-25-((tert-Butyldimethylsilyl)oxy)-17-(((tert-butyldimethylsilyl)oxy)methyl)-21-((tert-butyldiphenylsilyl)oxy)-11-hydroxy-13-(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-5-methylene-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl octanoate

  • Compound C67H102O15Si2

    (3S,7R,8E,11S,12S,13E,15S,17R,21R,23S,25S)-25-Acetoxy-17-(((tert-butyldimethylsilyl)oxy)methyl)-21-((tert-butyldiphenylsilyl)oxy)-11-hydroxy-1-methoxy-13-(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-5-methylene-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl octanoate

  • Compound C63H96O13Si2

    (1S,3R,7R,8E,11S,12S,13E,15S,17R,21R,23S)-17-(((tert-Butyldimethylsilyl)oxy)methyl)-21-((tert-butyldiphenylsilyl)oxy)-11-hydroxy-13-(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-5,19-dioxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl octanoate

  • Compound C69H110O14Si3

    (1S,3R,7R,8E,11S,12S,13E,15S,17R,21R,23R,25S)-25-((tert-Butyldimethylsilyl)oxy)-17-(((tert-butyldimethylsilyl)oxy)methyl)-21-((tert-butyldiphenylsilyl)oxy)-11-hydroxy-13-(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-5,19-dioxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl octanoate

  • Compound C66H100O16Si2

    (3S,7R,8E,11S,12S,13E,15S,17R,21R,23S,25S)-25-Acetoxy-17-(((tert-butyldimethylsilyl)oxy)methyl)-21-((tert-butyldiphenylsilyl)oxy)-11-hydroxy-1-methoxy-13-(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-5,19-dioxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl octanoate

  • Compound C50H82O14Si

    (2E)-Dimethyl 2,2'-((1S,3S,7R,11S,12S,15S,17R,21R,23S,E)-17-(((tert-butyldimethylsilyl)oxy)methyl)-11,21-dihydroxy-10,10,26,26-tetramethyl-12-(octanoyloxy)-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-ene-5,13-diylidene)diacetate

  • Compound C56H96O15Si2

    (2E)-Dimethyl 2,2'-((1S,3S,7R,11S,12S,15S,17R,21R,23R,25S,E)-25-((tert-butyldimethylsilyl)oxy)-17-(((tert-butyldimethylsilyl)oxy)methyl)-11,21-dihydroxy-10,10,26,26-tetramethyl-12-(octanoyloxy)-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-ene-5,13-diylidene)diacetate

  • Compound C53H86O17Si

    (2E)-Dimethyl 2,2'-((3S,7R,11S,12S,15S,17R,21R,23R,25S,E)-25-acetoxy-17-(((tert-butyldimethylsilyl)oxy)methyl)-11,21-dihydroxy-1-methoxy-10,10,26,26-tetramethyl-12-(octanoyloxy)-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-ene-5,13-diylidene)diacetate

  • Compound C44H68O15

    (2Z,2'E)-Dimethyl 2,2'-((3S,7R,11S,12S,15S,17R,21R,23R,25S,E)-11,21,25-trihydroxy-17-(hydroxymethyl)-10,10,26,26-tetramethyl-12-(octanoyloxy)-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-ene-5,13-diylidene)diacetate

  • Compound C46H70O6Si2

    (R)-Ethyl 4-((2S,6S)-6-((S)-4-(benzyloxy)-2-((tert-butyldiphenylsilyl)oxy)butyl)-3,3-dimethyltetrahydro-2H-pyran-2-yl)-3-((triethylsilyl)oxy)butanoate

  • Compound C52H84O7Si3

    (R)-Ethyl 4-((2S,4S,6R)-6-((S)-4-(benzyloxy)-2-((tert-butyldiphenylsilyl)oxy)butyl)-4-((tert-butyldimethylsilyl)oxy)-3,3-dimethyltetrahydro-2H-pyran-2-yl)-3-((triethylsilyl)oxy)butanoate

  • Compound C42H72O4Si3

    (S)-3-((tert-Butyldiphenylsilyl)oxy)-4-((2S,6S)-5,5-dimethyl-6-((S)-2-((triethylsilyl)oxy)-4-((trimethylsilyl)methyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-yl)butan-1-ol

  • Compound C48H86O5Si4

    (S)-4-((2R,4S,6S)-4-((tert-Butyldimethylsilyl)oxy)-5,5-dimethyl-6-((S)-2-((triethylsilyl)oxy)-4-((trimethylsilyl)methyl)pent-4-en-1-yl)tetrahydro-2H-pyran-2-yl)-3-((tert-butyldiphenylsilyl)oxy)butan-1-ol

  • Compound C44H68O14

    (2E,2'E)-Dimethyl 2,2'-((1S,3S,7R,11S,12S,15S,17R,21R,23S,E)-11,21-dihydroxy-17-(hydroxymethyl)-10,10,26,26-tetramethyl-12-(octanoyloxy)-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-ene-5,13-diylidene)diacetate

  • Compound C44H68O15

    (2E,2'E)-Dimethyl 2,2'-((1S,3S,7R,11S,12S,15S,17R,21R,23R,25S,E)-11,21,25-trihydroxy-17-(hydroxymethyl)-10,10,26,26-tetramethyl-12-(octanoyloxy)-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-ene-5,13-diylidene)diacetate

  • Compound C46H70O17

    (2E,2'E)-Dimethyl 2,2'-((3S,7R,11S,12S,15S,17R,21R,23R,25S,E)-25-acetoxy-1,11,21-trihydroxy-17-(hydroxymethyl)-10,10,26,26-tetramethyl-12-(octanoyloxy)-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-ene-5,13-diylidene)diacetate

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Acknowledgements

This research was supported by the National Institutes of Health (CA31845 to P.A.W., AI070010 to J.A.Z.) and the UCLA Center for AIDS Research (AI028697). Additional funding was provided by the ACS Division of Organic Chemistry Graduate Fellowship sponsored by Bristol-Myers Squibb, the Eli Lilly Organic Chemistry Graduate Fellowship, and the Stanford University Center for Molecular Analysis and Design.

Author information

Author notes

    • Brian A. DeChristopher
    • , Brian A. Loy
    • , Matthew D. Marsden
    •  & Adam J. Schrier

    These authors contributed equally to this work

Affiliations

  1. Departments of Chemistry and of Chemical and Systems Biology, Stanford University, Stanford, California, 94305, USA

    • Brian A. DeChristopher
    • , Brian A. Loy
    • , Adam J. Schrier
    •  & Paul A. Wender
  2. Department of Medicine, Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, California, 90095, USA

    • Matthew D. Marsden
    •  & Jerome A. Zack

Authors

  1. Search for Brian A. DeChristopher in:

  2. Search for Brian A. Loy in:

  3. Search for Matthew D. Marsden in:

  4. Search for Adam J. Schrier in:

  5. Search for Jerome A. Zack in:

  6. Search for Paul A. Wender in:

Contributions

B.A.D., B.A.L., M.D.M., A.J.S., J.A.Z. and P.A.W. conceived and designed the experiments. B.A.D., B.A.L., M.D.M. and A.J.S. performed the experiments and analysed the data. B.A.L., M.D.M., A.J.S. and P.A.W. co-wrote the paper. All authors commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jerome A. Zack or Paul A. Wender.

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Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nchem.1395

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