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Synthesis and antibacterial activity of pentacyclines: a novel class of tetracycline analogs.

Sun C, Hunt DK, Clark RB, Lofland D, O'Brien WJ, Plamondon L, Xiao XY - J. Med. Chem. (2011)

Bottom Line: Employing a highly efficient total synthesis approach, we synthesized and evaluated for antibacterial activity diverse and novel pentacycline analogs with systematic variations at C7, C8, C9, and C10.Certain substitution groups, as well as substitution patterns at various positions, were found to be preferred for increased antibacterial activity.A number of pentacycline analogs displayed potent activity in vitro and in vivo, especially against Gram-positive organisms.

View Article: PubMed Central - PubMed

Affiliation: Tetraphase Pharmaceuticals, Watertown, MA 02472, USA.

ABSTRACT
Employing a highly efficient total synthesis approach, we synthesized and evaluated for antibacterial activity diverse and novel pentacycline analogs with systematic variations at C7, C8, C9, and C10. Certain substitution groups, as well as substitution patterns at various positions, were found to be preferred for increased antibacterial activity. A number of pentacycline analogs displayed potent activity in vitro and in vivo, especially against Gram-positive organisms. Several analogs have also shown promising oral bioavailability in rats and cynomolgus monkey.

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Synthesis of pentacyclines via Michael–Dieckmann annulations.
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fig2: Synthesis of pentacyclines via Michael–Dieckmann annulations.

Mentions: Myers et al.12,17 recently reported a series of pentacyclic analogs with promising antibacterial activity against both Gram-positive and Gram-negative organisms. These analogs were based on a “pentacycline” scaffold (9, Figure 2),12,17 which has an additional benzene ring (E-ring) fused in a linear fashion to the C8 and C9 carbons on the tetracycline D-ring. The added E-ring not only produces a unique tetracycline scaffold but also presents several additional derivatization sites believed to have minimum effect on ribosomal binding as expected from the binding mode of tetracycline with the 30S ribosome. We believe this unique pentacyclic scaffold, coupled with optimal substitutions and substitution patterns, has the potential to uncover new tetracycline analogs that are potent, are capable of overcoming tetracycline resistance, and have improved pharmacological properties such as oral bioavailability. We therefore decided to expand the pentacycline series to include a much wider range of substitutions and substitution patterns. We evaluated the antibacterial activity of the new pentacycline analogs against a wide range of organisms including Gram-positive, Gram-negative, and tetracycline-resistant strains. We also studied in vivo efficacy and pharmacokinetic properties of several new pentacycline analogs in appropriate mouse, rat, and monkey models.


Synthesis and antibacterial activity of pentacyclines: a novel class of tetracycline analogs.

Sun C, Hunt DK, Clark RB, Lofland D, O'Brien WJ, Plamondon L, Xiao XY - J. Med. Chem. (2011)

Synthesis of pentacyclines via Michael–Dieckmann annulations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108469&req=5

fig2: Synthesis of pentacyclines via Michael–Dieckmann annulations.
Mentions: Myers et al.12,17 recently reported a series of pentacyclic analogs with promising antibacterial activity against both Gram-positive and Gram-negative organisms. These analogs were based on a “pentacycline” scaffold (9, Figure 2),12,17 which has an additional benzene ring (E-ring) fused in a linear fashion to the C8 and C9 carbons on the tetracycline D-ring. The added E-ring not only produces a unique tetracycline scaffold but also presents several additional derivatization sites believed to have minimum effect on ribosomal binding as expected from the binding mode of tetracycline with the 30S ribosome. We believe this unique pentacyclic scaffold, coupled with optimal substitutions and substitution patterns, has the potential to uncover new tetracycline analogs that are potent, are capable of overcoming tetracycline resistance, and have improved pharmacological properties such as oral bioavailability. We therefore decided to expand the pentacycline series to include a much wider range of substitutions and substitution patterns. We evaluated the antibacterial activity of the new pentacycline analogs against a wide range of organisms including Gram-positive, Gram-negative, and tetracycline-resistant strains. We also studied in vivo efficacy and pharmacokinetic properties of several new pentacycline analogs in appropriate mouse, rat, and monkey models.

Bottom Line: Employing a highly efficient total synthesis approach, we synthesized and evaluated for antibacterial activity diverse and novel pentacycline analogs with systematic variations at C7, C8, C9, and C10.Certain substitution groups, as well as substitution patterns at various positions, were found to be preferred for increased antibacterial activity.A number of pentacycline analogs displayed potent activity in vitro and in vivo, especially against Gram-positive organisms.

View Article: PubMed Central - PubMed

Affiliation: Tetraphase Pharmaceuticals, Watertown, MA 02472, USA.

ABSTRACT
Employing a highly efficient total synthesis approach, we synthesized and evaluated for antibacterial activity diverse and novel pentacycline analogs with systematic variations at C7, C8, C9, and C10. Certain substitution groups, as well as substitution patterns at various positions, were found to be preferred for increased antibacterial activity. A number of pentacycline analogs displayed potent activity in vitro and in vivo, especially against Gram-positive organisms. Several analogs have also shown promising oral bioavailability in rats and cynomolgus monkey.

Show MeSH