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    COMPOSITIONS AND ASSOCIATED METHODS OF MESOPOROUS NANOPARTICLES COMPRISING PLATINUM-ACRIDINE MOLECULES
    4.
    发明申请
    COMPOSITIONS AND ASSOCIATED METHODS OF MESOPOROUS NANOPARTICLES COMPRISING PLATINUM-ACRIDINE MOLECULES 审中-公开

    公开(公告)号：US20190290685A1

    公开(公告)日：2019-09-26

    申请号：US16345264

    申请日：2017-10-27

    Applicant: Wake Forest University

    Inventor： Ulrich Bierbach ,  Ye Zheng ,  Ravi Singh

    IPC: A61K33/243 ,  A61K9/51 ,  A61P35/00

    Abstract: Large-pore mesoporous silica nanoparticles (MSN) were prepared and functionalized to serve as a robust and biocompatible delivery platform for platinum-acridine (PA) anticancer agents. The material showed a high loading capacity for the dicationic, hydrophilic hybrid agent [PtCl(en)(N-[acridin-9-ylaminoethyl]-N-methylropionamidine)] dinitrate salt (P1 Al) and virtually complete retention of payload at neutral pH in a high-chloride buffer. In acidic media mimicking the pH inside the cells' lysosomes, rapid, burst-like release of P1 A1 from the nanoparticles is observed. Coating of the materials in phospholipid bilayers resulted in nanoparticles with greatly improved colloidal stability. The lipid and carboxylate- modified nanoparticles containing 40 wt. % drug caused S phase arrest and inhibited cell proliferation in pancreatic cancer cells at submicromolar concentrations similar to carrier-free P1A1. One feature of the nanoparticle-delivered P1A1 was that the payload did not escape from the acidified lysosomal vesicles into the cytoplasm, but was shuttled to the nuclear membrane and released into the nucleus.

    Functionalized Tyrosine Kinase Inhibitors Modified with Precious Metal Electrophiles and Methods Associated Therewith
    5.
    发明申请
    Functionalized Tyrosine Kinase Inhibitors Modified with Precious Metal Electrophiles and Methods Associated Therewith 审中-公开

    公开(公告)号：US20170081293A1

    公开(公告)日：2017-03-23

    申请号：US15126443

    申请日：2015-03-15

    Applicant: WAKE FOREST UNIVERSITY

    Inventor： Ulrich Bierbach ,  Mu Yang ,  Amanda J Pickard

    IPC: C07D239/94 ,  C07F15/00 ,  C07F1/00

    CPC classification number: C07D239/94 ,  C07F1/005 ,  C07F15/0093

    Abstract: Newly synthesized thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives have been studied as terminal carrier ligands in linear gold(I) complexes. The molecules mimic the tyrosine kinase inhibitor gefitinib (by computational docking experiments). Thiourea groups were either directly attached to quinazoline-C6 or linked to this position via a flexible ethylamino chain. One compound tested acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving an unusual dinuclear complex as determined by X-ray crystallography and/or electrospray mass spectrometry. One compound formed the desired stable linear complex. The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. One compound that was tested partially overcomes resistance to gefitinib in NCI-H1975 (with IC50 values of 1.7 and 30 μM, respectively), and the corresponding gold complex (13) maintains activity in the low-micromolar concentration range.

    Functionalized tyrosine kinase inhibitors modified with precious metal electrophiles and methods associated therewith
    7.
    发明授权
    Functionalized tyrosine kinase inhibitors modified with precious metal electrophiles and methods associated therewith 有权

    公开(公告)号：US10047057B2

    公开(公告)日：2018-08-14

    申请号：US15126443

    申请日：2015-03-15

    Applicant: WAKE FOREST UNIVERSITY

    Inventor： Ulrich Bierbach ,  Mu Yang ,  Amanda J Pickard

    IPC: C07D239/94 ,  C07F15/00 ,  C07F1/00

    Abstract: Newly synthesized thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives have been studied as terminal carrier ligands in linear gold(I) complexes. The molecules mimic the tyrosine kinase inhibitor gefitinib (by computational docking experiments). Thiourea groups were either directly attached to quinazoline-C6 or linked to this position via a flexible ethylamino chain. One compound tested acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving an unusual dinuclear complex as determined by X-ray crystallography and/or electrospray mass spectrometry. One compound formed the desired stable linear complex. The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. One compound that was tested partially overcomes resistance to gefitinib in NCI-H1975 (with IC50 values of 1.7 and 30 μM, respectively), and the corresponding gold complex (13) maintains activity in the low-micromolar concentration range.

    Cleavable conjugates of functionalized platinum-acridine and platinum-benzacridine agents and methods thereof
    8.
    发明授权
    Cleavable conjugates of functionalized platinum-acridine and platinum-benzacridine agents and methods thereof 有权

    公开(公告)号：US09765103B2

    公开(公告)日：2017-09-19

    申请号：US15321578

    申请日：2015-06-22

    Applicant: WAKE FOREST UNIVERSITY

    Inventor： Ulrich Bierbach ,  Song Ding

    IPC: A61K31/555 ,  C07F15/00

    CPC classification number: C07F15/0093 ,  C07D219/12 ,  C07D221/18 ,  C07D487/06

    Abstract: The present invention relates to using a versatile synthetic approach to generate a new class of ester, amido, or carbamate prodrugs of highly potent, but systemically too toxic, platinum-acridine anticancer agents. The new hybrids contain a hydroxyl group, which has been masked with a cleavable lipophilic acyl moiety. Both butanoic (butyric) and bulkier 2-propanepentanoic (valproic) esters were introduced to these compounds. The goal of this design was to improve the drug-like properties of the pharmacophore (e. g., log D) without compromising its DNA-mediated cell kill potential. Two distinct pathways by which the target compounds undergo effective ester hydrolysis, the proposed activating step, have been confirmed: platinum-mediated, self-immolative ester cleavage in a low-chloride environment (LC-ESMS, NMR spectroscopy) and enzymatic cleavage by human carboxylesterase-2 (hCES-2) (LC-ESMS). Several of the new compounds show excellent stability, reduced systemic toxicity, and favorable activation profiles while maintaining submicromolar cytotoxicity in various cancers, such as lung adenocarcinoma cell lines (A549, NCI-H1435). The results suggest that the novel dual-mode prodrug concept may have the potential to hasten the preclinical development of platinum-acridines.

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