Dataset Information

Recent progress in the strategic incorporation of fluorine into medicinally active compounds.

ABSTRACT: This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to (i) taxoid anticancer agents, (ii) acylhydrazone-based antifungal agents and (iii) inhibitors of matrix metalloproteinase 9 (MMP9) for medicinal chemistry and chemical biology studies. In the case study (i), a series of next-generation fluorotaxoids, bearing m-OCF3 or m-OCF2H group in the C2-benzoate moiety was designed, synthesized and examined for their potencies. A number of these fluorotaxoids possess two orders of magnitude greater potency in different drug-resistant cancer cell lines as compared to paclitaxel. One of these next-generation fluorotaxoids, SB--121205wasselected for detailed mechanistic study against highly paclitaxel-resistant human breast cancer cell line, MCF-7/PTX, which disclosed a unique mechanism of action. Recently, glucosylceramide (GlcCer) synthesis emerged as a promising target for next-generation antifungal agents, especially against cryptococcosis, candidiasis and pulmonary aspergillosis. The HTP screening of compound libraries identified several acylhydrazones as hit compounds. In the case study (ii), fluoro-acylhydrazones containing F, OCF3, OCHF2, o-F/p-OCF3, as well as o-F/p-CF3 functional groups in the ring A and ring B were designed based on these hit compounds, synthesized and examined for their potencies against C. neoformans. A number of those novel fluoro-acylhydrazones exhibited high potency and excellent killing properties. The hemopexin-like domain of matrix metalloproteinases (MMPs) is a highly promising target to circumvent the critical issue in the development of MMP inhibitors for the treatment of various cancers. In the case study (iii), a small optimization library of compounds, based on the OCHF2-containing hit compound, SB-M-001, was generated and evaluated, which identified a fluorine-containing new lead compound, SB-M-103. SB-M-103 was found to inhibit tumor cell growth, migration, and invasion by effectively disrupting the MMP-9 homodimerization.

SUBMITTER: Haranahalli K

PROVIDER: S-EPMC6752223 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Recent progress in the strategic incorporation of fluorine into medicinally active compounds.

Haranahalli Krupanandan K Honda Tadashi T Ojima Iwao I

Journal of fluorine chemistry 20181103

This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to (i) taxoid anticancer agents, (ii) acylhydrazone-based antifungal agents and (iii) inhibitors of matrix metalloproteinase 9 (MMP9) for medicinal chemistry and chemical biology studies. In the case study (i), a series of next-generation fluorotaxoids, bearing m-OCF3 or m-OCF2H group in the C2-benzoate moiety was designed, synthesized and examined ...[more]

PMID: 31537946

Similar Datasets

Project description:Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as "inhibitors," which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was "Immune Tolerance Induction," consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ~30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to "bypass" the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

Dataset Information

Recent progress in the strategic incorporation of fluorine into medicinally active compounds.

Publications

Recent progress in the strategic incorporation of fluorine into medicinally active compounds.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets