Ketolides (3-keto) such as TE-802 and acylides (3-O-acyl) like TEA0929 are ineffective against constitutively resistant pathogens harboring erythromycin ribosomal methylation (erm) genes. Following our previous work on alkylides (3-O-alkyl), we explored the structure-activity relationships of hybrids combining (R/S) 3-descladinosyl erythromycin with 6/7-quinolone motifs, featuring extended ether-linked spacers, with a focus on their efficacy against pathogens bearing constitutive erm gene resistance. Optimized compounds 17a and 31f not only reinstated efficacy against inducibly resistant pathogens but also demonstrated significantly augmented activities against constitutively resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes, which are typically refractory to existing C-3 modified macrolides. Notably, hybrid 31f (coded ZN-51) represented a pioneering class of agents distinguished by its dual modes of action, with ribosomes as the primary target and topoisomerases as the secondary target. As a novel chemotype of macrolide-quinolone hybrids, alkylide 31f is a valuable addition to our armamentarium against macrolide-resistant bacteria.

24 Sep 2012·SmallQ2 · MATERIALS SCIENCE

Small Molecule–Gold Nanorod Conjugates Selectively Target and Induce Macrophage Cytotoxicity towards Breast Cancer Cells

Q2 · MATERIALS SCIENCE

Article

Author: Mostafa A. El-Sayed ; Adegboyega K. Oyelere ; Erik C. Dreaden ; Matthew J. Kieffer ; Lauren A. Austin ; Sandra C. Mwakwari

Gold nanoparticles are known to activate anti-tumor potential in macrophage immune cells; however, the subsequent effects of these cells on others nearby are poorly understood. A novel gold-nanoparticle conjugate that selectively targets and induces cytotoxic activity of tumor-associated macrophages towards breast cancer cells in co-culture is synthesized. These constructs are promising new tools for studying fundamental biological interactions with nanoscale materials and candidates for emerging macrophage-mediated delivery applications.

26 Aug 2010·Journal of Medicinal ChemistryQ1 · MEDICINE

Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton

Q1 · MEDICINE

Article

Author: Gurard-Levin, Zachary A. ; Mrksich, Milan ; Oyelere, Adegboyega K. ; Khan, Shabana I. ; Mwakwari, Sandra C. ; Patil, Vishal ; Tekwani, Babu L. ; Guerrant, William

Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors' macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity.

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Preclinical	Japan	-	-
Bacterial Infections	Preclinical	Japan	-	-

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