Abstract

A series of analogs of the potent HIV-1 integrase (HIV IN) inhibitor chicoric acid (CA) was designed with the intention of ameliorating some of the parent natural product’s undesirable properties, in particular its toxicity, instability, and poor membrane permeability. More than 70 analogs were synthesized and assayed for three types of activity: (1) the ability to inhibit 3′-end processing and strand transfer reactions using recombinant HIV IN in vitro, (2) toxicity against the CD4+ lymphoblastoid cell line, MT2, and (3) anti-HIV activity against HIV_LAI. CA analogs lacking one of the carboxyl groups of CA and with 3,4,5-trihydroxycinnamoyl sidechains in place of the caffeoyl group of CA exhibited the most potent inhibition of HIV replication and end-processing activity. Galloyl-substituted derivatives also displayed very potent in vitro and in vivo activities, in most cases exceeding the inhibitory effects of CA itself. Conversely, analogous monocarboxy caffeoyl analogs exhibited only modest inhibition, while the corresponding 3,4-dihydroxybenzoyl-substituted compounds were devoid of activity.

Graphical abstract

A series of analogs of the potent HIV-1 integrase (HIV IN) inhibitor chicoric acid (CA) was designed with the intention of ameliorating some of the parent natural product’s undesirable properties, in particular its toxicity, instability, and poor membrane permeability. More than 70 analogs were synthesized and assayed for three types of activity: (1) inhibition of 3′-end processing and strand transfer reactions in vitro, (2) toxicity against a CD4+ lymphoblastoid cell line, and (3) anti-HIV activity against HIV_LAI.

Keywords: HIV integrase; Chicoric acid; SAR

Article Outline

1. Introduction

2. Chemistry

2.1. Synthesis of chicoric acid analogs with increased stability

2.2. Synthesis of chicoric acid analogs with improved stability and membrane permeability

3. Biology

4. Results and discussion

5. Conclusions

6. Experimental

6.1. General information

6.2. Inhibition of integrase

6.3. Cell toxicity and anti-HIV activities of CA analogs

6.4. Preparatory HPLC purification

6.5. Analytical HPLC analysis

6.6. (dl)-2,3-Diaminopropionic acid methyl ester dihydrochloride (6)

6.7. (dl)-2,4-Diaminobutyric acid methyl ester dihydrochloride (7)

6.8. (dl)-2,5-diaminopentanoic acid methyl ester dihydrochloride (8)

6.9. l-2,6-Diaminohexanoic acid methyl ester dihydrochloride (9)

6.10. (dl)-2,3-Bis(3,4-dimethoxycarbonyloxybenzoylamino)propionic acid (13)

6.11. (dl)-2,3-Bis(3,4,5-trimethoxycarbonyloxybenzoylamino)propionic acid (14)

6.12. (dl)-2,3-Bis[3-(3,4-dimethoxycarbonyloxyphenyl)acryloylamino]propionic acid (15)

6.13. (dl)-2,4-Bis(3,4-dimethoxycarbonyloxybenzoylamino)butyric acid (16)

6.14. (dl)-2,4-Bis(3,4,5-trimethoxycarbonyloxybenzoylamino)butyric acid (17)

6.15. (dl)-2,4-Bis[3-(3,4-dimethoxycarbonyloxyphenyl)acryloylamino]butyric acid (18)

6.16. (dl)-2,5-Bis(3,4-dimethoxycarbonyloxybenzoylamino)pentanoic acid (19)

6.17. (dl)-2,5-Bis(3,4,5-trimethoxycarbonyloxybenzoylamino)pentanoic acid (20)

6.18. (dl)-2,5-Bis[3-(3,4-dimethoxycarbonyloxyphenyl)acryloylamino]pentanoic acid (21)

6.19. l-2,6-Bis(3,4-dimethoxycarbonyloxybenzoylamino)hexanoic acid (22)

6.20. l-2,6-Bis(3,4,5-trimethoxycarbonyloxybenzoylamino)hexanoic acid (23)

6.21. l-2,6-Bis[3-(3,4-dimethoxycarbonyloxyphenyl)acryloylamino]hexanoic acid (24)

6.22. (dl)-2,3-Bis(3,4-dihydroxybenzoylamino)propionic acid (25)

6.23. (dl)-2,3-Bis(3,4,5-trihydroxybenzoylamino)propionic acid (26)

6.24. (dl)-2,3-Bis[3-(3,4-dihydroxyphenyl)acryloylamino]propionic acid (27)

6.25. (dl)-2,4-Bis(3,4-dihydroxybenzoylamino)butyric acid (28)

6.26. (dl)-2,4-Bis(3,4,5-trihydroxybenzoylamino)butyric acid (29)

6.27. (dl)-2,4-Bis[3-(3,4-dihydroxyphenyl)acryloylamino]butyric acid (30)

6.28. (dl)-2,5-Bis(3,4-dihydroxybenzoylamino)pentanoic acid (31)

6.29. (dl)-2,5-Bis(3,4,5-trihydroxybenzoylamino)pentanoic acid (32)

6.30. (dl)-2,5-Bis[3-(3,4-dihydroxyphenyl)acryloylamino]pentanoic acid (33)

6.31. l-2,6-Bis(3,4-dihydroxybenzoylamino)hexanoic acid (34)

6.32. l-2,6-Bis(3,4,5-trihydroxybenzoylamino)hexanoic acid (35)

6.33. l-2,6-Bis[3-(3,4-dihydroxyphenyl)acryloylamino]hexanoic acid (36)

6.34. (dl)-2,3-Bis[3-(3,4,5-trimethoxyphenyl)acryloylamino]propionic acid methyl ester (38)

6.35. (dl)-2,3-Bis[3-(3,4,5-trihydroxyphenyl)acryloylamino]propionic acid (42)

6.36. (dl)-2,4-Bis[3-(3,4,5-trihydroxyphenyl)acryloylamino]butyric acid (43)

6.37. (dl)-2,5-Bis[3-(3,4,5-trihydroxyphenyl)acryloylamino]pentanoic acid (44)

6.38. l-2,6-Bis[3-(3,4,5-trihydroxyphenyl)acryloylamino]hexanoic acid (45)

6.39. (dl)-2,3-Bis(3,4,5-trimethoxybenzoylamino)propionic acid methyl ester (48)

6.40. (dl)-2,3-Bis[3-(3,4-dimethoxyphenyl)acryloylamino]propionic acid methyl ester (49)

6.41. (dl)-2,3-Bis(3,4,5-trimethoxybenzoylamino)propionic acid (50)

6.42. (dl)-2,3-Bis[3-(3,4-dimethoxyphenyl)acryloylamino]propionic acid (51)

6.43. (dl)-2,3-Bis[3-(3,4,5-trimethoxyphenyl)acryloylamino]propionic acid (52)

6.44. (dl)-2,3-Bis(3,4-dihydroxybenzoylamino)propionic acid methyl ester (56)

6.45. (dl)-2,3-Bis(3,4,5-trihydroxybenzoylamino)propionic acid methyl ester (57)

6.46. (dl)-2,3-Bis[3-(3,4-dihydroxyphenyl)acryloylamino]propionic acid methyl ester (58)

6.47. (dl)-2,4-Bis(3,4-dihydroxybenzoylamino)butyric acid methyl ester (59)

6.48. (dl)-2,4-Bis(3,4,5-trihydroxybenzoylamino)butyric acid methyl ester (60)

6.49. (dl)-2,4-Bis[3-(3,4-dihydroxyphenyl)acryloylamino]butyric acid methyl ester (61)

6.50. (dl)-2,5-Bis(3,4-dihydroxybenzoylamino)pentanoic acid methyl ester (62)

6.51. (dl)-2,5-Bis(3,4,5-trihydroxybenzoylamino)pentanoic acid methyl ester (63)

6.52. (dl)-2,5-Bis[3-(3,4-dihydroxyphenyl)acryloylamino]pentanoic acid methyl ester (64)

6.53. l-2,6-Bis(3,4-dihydroxybenzoylamino)hexanoic acid methyl ester (65)

6.54. l-2,6-Bis(3,4,5-trihydroxybenzoylamino)hexanoic acid methyl ester (66)

6.55. l-2,6-Bis[3-(3,4-dihydroxyphenyl)acryloylamino]hexanoic acid methyl ester (67)

Acknowledgements

References