A series of erythromycin A-derived semisynthetic antibiotics, featuring incorporation of a basic nitrogen atom into a ring expanded (15-membered) macrocyclic lactone, have been prepared and biologically evaluated. Semisynthetic modifications focused upon (1) varied substitution at the macrocyclic ring nitrogen and (2) epimerization or amine substitution at the C-4" hydroxyl site within the cladinose sugar. In general, the new azalides exhibit improved Gram-negative potency, expanding the spectrum of erythromycin A to fully include Haemophilus influenzae and Neisseria gonorrhoeae. Whencompared to erythromycin A, the azalides exhibit substantially increased half-life and area-under-the-curve values in all species studied. The overall in vitro/in vivo performance of TV-methyl, C-4" epimers 3a and 9; and C-4" amine ll identify these compounds as the most interesting erythromycin Asuperior agents. Compound3a has been advanced to clinical study. 1029Erythromycin A is a widely used antibiotic in oral outpatient therapy, including pediatrics. It is frequently the agent of choice for treatment of respiratory, cutaneous, Chlamydia, and Campylobacter infections. However, erythromycin A is not indicated for the treatment of Haemophilus influenzae except with co-administration of sulfonamides. Erythromycin A is also unstable at gastric pH, and is poorly absorbed with oral dosing.In our effort to expand the antimicrobial spectrum and to improve upon the pharmacokinetic properties of erythromycin A, the syntheses of erythromycin A-derived 15-membered aza-macrolides depicted in Schemes 1 and 2 were undertaken. Herein are presented the antibacterial profiles of the series, which features varied alkyl substitution at the 9a-aza site within the macrocyclic ring, and modifications at the C-4" site within the cladinose sugar. Additionally, for selected compounds, antiinfective activity against Staphylococcus aureus in mice, and pharmacokinetic profiles in several species are presented.
Familial adenomatous polyposis (FAP) is a genetic disorder characterized by the development of hundreds of polyps throughout the colon. Without prophylactic colectomy, most individuals with FAP develop colorectal cancer at an early age. Treatment with EPA in the free fatty acid form (EPA-FFA) has been shown to reduce polyp burden in FAP patients. Since high-purity EPA-FFA is subject to rapid oxidation, a stable form of EPA compound has been developed in the form of magnesium l-lysinate bis-eicosapentaenoate (TP-252). We assessed the chemopreventive efficacy of TP-252 on intestinal tumor formation using ApcΔ14/+ mice and compared it with EPA-FFA. TP-252 was supplemented in a modified AIN-93G diet at 1, 2 or 4% and EPA-FFA at 2.5% by weight and administered to mice for 11 weeks. We found that administration of TP-252 significantly reduced tumor number and size in the small intestine and colon in a dose-related manner and as effectively as EPA-FFA. To gain further insight into the cancer protection afforded to the colon, we performed a comprehensive lipidomic analysis of total fatty acid composition and eicosanoid metabolites. Treatment with TP-252 significantly decreased the levels of arachidonic acid (AA) and increased EPA concentrations within the colonic mucosa. Furthermore, a classification and regression tree (CART) analysis revealed that a subset of fatty acids, including EPA and docosahexaenoic acid (DHA), and their downstream metabolites, including PGE3 and 14-hydroxy-docosahexaenoic acid (HDoHE), were strongly associated with antineoplastic activity. These results indicate that TP-252 warrants further clinical development as a potential strategy for delaying colectomy in adolescent FAP patients.
Chemical modification of the macrolide antibiotic oleandomycin (C-1) is described. Reductive amination of 11-acetyl-4"-deoxy-4"-oxo-oleandomycin (C-6) with ammonium acetate provides amino-oleandomycin derivative C-7 in which the 4"-amine is oriented in the axial configuration. The structure-activity relationship of a series of 4"-sulfonamide analogs prepared from amino-oleandomycin derivative C-7 is discussed. Noteworthy is the significant in vitro potency enhancement of the para-chlorobenzenesulfonamide analog C-12 over that of the parent oleandomycin. The absolute configuration of the 4"-amino-oleandomycin derivative C-7 was established through X-ray analysis of the para-iodobenzenesulfonamide analog C-14.
Background: TP317 is a novel, highly stable chelate salt of resolvin E1 (RvE1), a pro-resolution mediator that stimulates myeloid cell phagocytosis of tumor debris and attenuates pro-tumoral inflammation through activation of the GPCR, ChemR23 (Sulciner et al., 2018, J. Exp. Med). We hypothesized that RvE1 shifts the immunosuppressive tumor microenvironment (TME) to an immunogenic state, thus offering combination potential with immune checkpoint inhibitors (ICI) in ICI-resistant and ICI-sensitive tumors. Methods: Subcutaneous murine models of lung (LLC), melanoma (B16F10), and pancreatic (Panc02; KPC) tumors were used to investigate TP-317 monotherapy and combinations with ICI. Treatment was initiated when tumors reached 125-240 mm3. Results: In the LLC model (N=5/group), TP317 (0.75 µg QD) inhibited tumor growth (1419 ± 266 mm3) compared to placebo (2348 ± 542 mm3; p=0.068) and anti-PD1 (200 µg IP, Q3D; 3015 ± 730; p=0.078). TP317 + anti-PD1 dual therapy was superior to placebo and anti-PD1 alone (893 ± 166 mm3; p<0.05). In the B16F10 model (N=8/group), TP317 (7.5 µg Q6D) was efficacious compared to placebo (787 ± 367 vs 1964 ± 208 mm3; p<0.01) and comparable to the ICI dual therapy of anti-PD1 + anti-CTLA4 (100 µg 1st dose, 200 µg IP Q3D up to 4 doses). Triple therapy with TP317 + anti-PD1 + anti-CTLA4 was superior to ICI dual therapy (340 ± 91 vs 757 ± 260 mm3; p<0.05). In the Panc02 model (N=8/group), TP317 (0.75 µg Q7D) was efficacious compared to placebo (1148 ± 178 vs 1992 ±165 mm3; p<0.001) and comparable to anti-PD1. TP317 + anti-PD1 dual therapy demonstrated significant anti-tumor activity compared to anti-PD1 alone (329 ± 72 vs 1446 ± 305 mm3; p<0.01). In KRAS-mutant KPC tumors (N=10/group), TP317 (7.5 µg Q6D) demonstrated significant anti-tumor activity compared to placebo (500 ± 110 vs 1314 ± 106 mm3; p<0.001) and was comparable to anti-PD1, while TP-317 + anti-PD1 was superior to anti-PD1 alone (353 ± 82 vs 710 ± 106 mm3; p<0.01). In Panc02 and KPC models, TP317’s anti-tumor efficacy was attenuated by CD8+ T cell or NK cell depletion. Consistent with the depletion study results, RNAseq analysis with cell-type deconvolution showed that TP317 enhanced CD8 and NK cell associated programs in Panc02 and B16F10 tumors, and also promoted macrophage, dendritic cell, B cell and antigen presentation functions in the TME. Conclusions: TP317 monotherapy and ICI combinations significantly inhibited tumor growth in various murine models of cancer. The effects on various immune cell functions and the surprising efficacy of short half-life RvE1 (<2 hours) dosed weekly suggests that TP317 is reprogramming the TME to an immunogenic state. In summary, TP317, an RvE1 drug with a high therapeutic index, has potent single agent efficacy and offers a novel approach in combination with ICI to treat ICI-resistant and ICI-sensitive tumors. Citation Format: Franciele C. Kipper, Eva Rothenberger, Abigail Kelly, Michael Gillespie, Ahmed Attaya, Diane R. Bielenberg, Sui Huang, Lance Pflieger, Frank Sciavolino, Aaron Mathias, Wayne Klohs, John Parkinson, Gary Mathias, Dipak Panigrahy. TP317, a first-in-class resolvin E1 small molecule, potentiates the efficacy of immune checkpoint (ICI) inhibitors in ICI-resistant and ICI-sensitive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1135.
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