First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics

No Comments A decline in energy is common in aging, and the restoration of mitochondrial bioenergetics may offer a common approach for the treatment of numerous age-associated diseases. Cardiolipin is a unique phospholipid that is exclusively expressed on the inner mitochondrial membrane where it plays an important structural role in cristae formation and the organization of the respiratory complexes into supercomplexes for optimal oxidative phosphorylation. The interaction between cardiolipin and cytochrome c determines whether cytochrome c acts as an electron carrier or peroxidase. Cardiolipin peroxidation and depletion have been reported in a variety of pathological conditions associated with energy deficiency, and cardiolipin has been identified as a target for drug development. This review focuses on the discovery and development of the first cardiolipin-protective compound as a therapeutic agent. SS-31 is a member of the Szeto-Schiller (SS) peptides known to selectively target the inner mitochondrial membrane. SS-31 binds selectively to cardiolipin via electrostatic and hydrophobic interactions. By interacting with cardiolipin, SS-31 prevents cardiolipin from converting cytochrome c into a peroxidase while protecting its electron carrying function. As a result, SS-31 protects the structure of mitochondrial cristae and promotes oxidative phosphorylation. SS-31 represents a new class of compounds that can recharge the cellular powerhouse and restore bioenergetics. Extensive animal studies have shown that targeting such a fundamental mechanism can benefit highly complex diseases that share a common pathogenesis of bioenergetics failure. This review summarizes the mechanisms of action and therapeutic potential of SS-31 and provides an update of its clinical development programme. (Br J Pharmacol. 2014 Apr;171(8):2029-50.)

Phthalocyanine–Peptide Conjugates: Receptor-Targeting Bifunctional Agents for Imaging and Photodynamic Therapy

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The synthesis of a series of new zinc phthalocyanine–peptide conjugates targeting the gastrin-releasing peptide (GRP) and integrin receptors is reported. Two alternative synthetic methods based on Sonogashira cross-coupling of an iodinated zinc phthalocyanine with acetylenic bombesin or arginine–glycine–aspartic acid (RGD) derivatives, either in solution or on solid phase, are presented. The water-soluble conjugates were screened for their photodynamic efficacy against several cancer cell lines expressing different levels of GRP and integrin receptors, and their intracellular localization was evaluated via confocal fluorescence microscopy. Variations in photocytotoxicity between the conjugates correlate to differences in hydrophobicity as well as receptor-mediated cell uptake. In the case of the phthalocyanine–bombesin conjugate, competition experiments confirm the involvement of the GRP receptor in both the phototherapeutic activity as well as intracellular localization. These findings warrant further in vivo studies to evaluate the potential of this conjugate as photosensitizer for photodynamic therapy (PDT) of cancers overexpressing the GRP receptor. (J. Med. Chem. 2013, 56, 4, 1520–1534.)

Synthesis and evaluation of novel dolastatin 10 derivatives for versatile conjugations

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Dolastatin 10 ( purchase Pregabalin 1) is a highly potent cytotoxic microtubule inhibitor (cytotoxicity IC50 < 5.0 nM) and several of its analogs have recently been used as payloads in antibody drug conjugates. Herein, we describe the design and synthesis of a series of novel dolastatin 10 analogs useful as payloads for conjugated drugs. We explored analogs containing functional groups at the thiazole moiety at the C-terminal of dolastatin 10. The functional groups included amines, alcohols, and thiols, which are representative structures used in known conjugated drugs. These novel analogs showed excellent potency in a tumor cell proliferation assay, and thus this series of dolastatin 10 analogs is suitable as versatile payloads in conjugated drugs. Insights into the structure–activity relationships of the analogs are also discussed.(Bioorganic & Medicinal Chemistry. Volume 26, Issue 8, 1 May 2018, Pages 1643-1652.)

Potential protective effect of Trans-10-hydroxy-2-decenoic acid on the inflammation induced by Lipoteichoic acid

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Royal jelly (RJ) is known as a functional food for its diverse health-beneficial properties and complicated chemical compositions. Trans-10-hydroxy-2-decenoic acid (10-HDA) is the exclusive lipid component in RJ. In the present study, the in vitro anti-inflammatory effect of 10-HDA in LTA (Lipoteichoic acid from Staphylococcus aureus) induced RAW 264.7 macrophages are evaluated. The results showed that 10-HDA had potent, dose-dependent inhibitory effects on the release of major inflammatory mediators and NO. Several key inflammatory genes, including IL-1β, IL-6, MCP-1 and COX-2 have also been suppressed by 10-HDA. Furthermore, the effects of 10-HDA on LTA-induced pulmonary damage were also examined in mice. It was found that the administration of 10-HDA (100 mg/kg) can provide protective effects by attenuating lung histopathological changes and modulating the secretion of LTA-stimulated inflammatory cytokines in mice, such as IL-10, MCP-1 and TNF-α. Conclusively, the results reveal the potent anti-inflammatory properties of 10-HDA and provide biological information for the future application.(Journal of Functional Foods. Volume 45, June 2018, Pages 491-498.)

Properties of octenyl succinic anhydride (OSA) modified starches and their application in low fat mayonnaise

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Wheat starch (WS), corn starch (CS), waxy corn starch (WCS), potato starch (PS), sweet potato (SP), rice starch (RS) and kidney bean (KB) were modified using octenyl succinic anhydride (OSA) and evaluated for various properties. Degree of substitution (DS) showed significant increase with increase in amylose (AM) content. OSA modified starches showed higher paste viscosities compared to their native counterparts. OSA groups acted majorly on the surface and caused some superficial pores, but crystalline pattern was not significantly altered for all starches. OSA modified starches were used in preparing low fat mayonnaise by substituting 75% fat. OSA modified starches enhanced the emulsifying properties of mayonnaise. Mayonnaises prepared using OSA modified starches were evaluated for phase separation, brightness (L*), color index (dE), and rheological parameters (G′ and G″). Mayonnaises prepared using OSA modified starches showed higher G’ and exhibited gel like structure. Fat substituted (FS) mayonnaise was preferred over full fat (FF) mayonnaise by the consumers. No significant effect of fat substitution was observed on particle size and phase separation for all mayonnaise samples. (International Journal of Biological Macromolecules.,Volume 131, 15 June 2019, Pages 147-157.)

Self-nanoemulsifying drug delivery systems as novel approach for pDNA drug delivery

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It was the aim of this study to investigate a novel strategy for oral gene delivery utilizing a self-nanoemulsifying drug delivery system (SNEDDS). After hydrophobic ion pairing a plasmid was incorporated into SNEDDS. The mean droplet size of resulting nanoemulsions was determined to be between 45.8 and 47.5 nm. A concentration dependent cytotoxicity of the formulations was found on HEK-293 cells via MTT assay. Degradation studies via DNase I showed that incorporation into SNEDDS led to significantly, up to 8-fold prolonged resistant time against enzymatic digestion compared to naked pDNA and pDNA–lipid complexes. Transfection studies carried out revealed a significantly improved transfection compared to naked pDNA. Further, no decrease in transfection efficiency compared to transfection using Lipofectin® transfection reagent was observed. (International Journal of Pharmaceutics. Volume 487, Issues 1–2, 20 June 2015, Pages 25-31.)

Impact of different hydrophobic ion pairs of octreotide on its oral bioavailability in pigs

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The objective of this study was to investigate the impact of different hydrophobic ion pairs (HIP) on the oral bioavailability of the model drug octreotide in pigs.

Octreotide was ion paired with the anionic surfactants deoxycholatedecanoate and docusate differing in lipophilicity. These hydrophobic ion pairs were incorporated in self-emulsifying drug delivery systems (SEDDS) based on BrijO10, octyldodecanol, propylene glycol and ethanol in a concentration of 5 mg/ml. SEDDS were characterized regarding size distribution, zeta potential, stability towards lipase, log DSEDDS/release medium and mucus diffusion behavior. The oral bioavailability of octreotide was evaluated in pigs via LC-MS/MS analyses.

Most efficient ion pairing was achieved at a molar ratio of 1:3 (peptide: surfactant). SEDDS containing the octreotide-deoxycholate, -decanoate and -docusate ion pair exhibited a mean droplet size of 152 nm, 112 nm and 191 nm and a zeta potential of − 3.7, − 4.6 and − 5.7 mV, respectively. They were completely stable towards degradation by lipase and showed a log DSEDDS/release medium of 1.7, 1.8 and 2.7, respectively. The diffusion coefficient of these SEDDS was in the range of 0.03, 0.11 and 0.17 × 10− 9 cm2/s, respectively. In vivo studies with these HIPs showed no improvement in the oral bioavailability in case of octreotide-decanoate. In contrast, octreotide-deoxycholate and octreotide-docusate SEDDS resulted in a 17.9-fold and 4.2-fold higher bioavailability vs. control.

According to these results, hydrophobic ion pairing could be identified as a key parameter for SEDDS to achieve high oral bioavailability. (Journal of Controlled Release. Volume 273, 10 March 2018, Pages 21-29.)

Perspectives on Biologically Active Camptothecin Derivatives

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Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.

Camptothecin (CPT) is a pentacyclic alkaloid isolated by Wall et al. in the early 1960s from the Chinese tree Camptotheca acuminata. This compound attracted immediate interest as a potential cancer chemotherapeutic agent due to its impressive activity against leukemias and various solid tumors in experimental systems. Due to CPT’s negligible water solubility, clinical trials were initiated using the water-soluble sodium salt of CPT in the early 1970s. The trials were suspended in the 1970s due to lower efficacy of 2, accompanied by unpredictable and severe levels of toxicity, including hemorrhagic cystitis and myelotoxicity. Interest in CPT then subsided for over a decade. Revived attention resulted from the breakthrough discovery of DNA topoisomerase I (Topo I) as a therapeutic target for CPT. This discovery put CPT back on the frontlines of anticancer drug development in the late 1980s. Accordingly, CPT’s total synthesis, mechanism of action, structure–activity relationship (SAR), analog synthesis as well as pharmacology, formulation, drug delivery, preclinical studies and clinical trials have been studied extensively. Recent interesting research approaches include using prodrug concepts and drug delivery systems for CPT.
As the result of these renewed research efforts, three CPT analogues, topotecan (TPT), irinotecan (CPT-11), and belotecan (CKD-602), received governmental approval for the clinical treatment of ovarian, small-cell lung, and refractory colorectal cancers. Three additional water-soluble analogues, exatecan (DX-8951f) lurtotecan (GG-211), and sinotecan, are currently under clinical evaluation. (Med Res Rev. 2015 Jul; 35(4): 753–789.)