Granted Patent
B2
US 12,509,468 · App. 17/426,932 · Granted Dec 30, 2025
Quindoline compounds and uses thereof
Inventors:
Laurence Hurley (Tucson, AZ); Biswanath De (Tucson, AZ); Venkateshwar R. Chappeta (Tucson, AZ); Tracy A. Brooks (Tucson, AZ); Vijay Gokhale (Tucson, AZ); Cynthia Miranti (Tucson, AZ); Elsa Reyes Reyes (Tucson, AZ)
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Abstract
This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a quindoline (or similar) structure which function as stabilizers of G-quadruplex (G4) formation, and their use as therapeutics for the treatment of cancer (e.g., castration-resistant prostate cancer), and other conditions mediated by G4 stabilization.
Claims (17)
1 . A compound described by Formula I:
including pharmaceutically acceptable salts, solvates, and/or prodrugs thereof;
wherein R 1 is hydrogen or methyl;
wherein R 2 is selected from hydrogen,
wherein R 3 is hydrogen or methyl;
wherein R 4 is selected from hydrogen,
wherein R 5 is selected from Hydrogen, Chlorine, Bromine,
wherein R 6 is selected from
2 . The compound of claim 1 , wherein the compound is selected from:
3 . A pharmaceutical composition comprising a compound of claim 1 .
4 . A method of treating a cancer selected from prostate cancer and colon cancer, comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition of claim 3 .
5 . The method of claim 4 , wherein administration of the pharmaceutical composition results in stabilization of G-quadruplex (G4) formation.
6 . The method of claim 4 , wherein the patient is a human patient.
7 . The method of claim 4 , further comprising
administering to said patient one or more anticancer agents, wherein said anticancer agent one or more of a chemotherapeutic agent, and radiation therapy, and/or
administering to said patient one or more anticancer agents.
8 . A kit comprising a compound of claim 1 and instructions for administering said compound to a patient having a disease or condition characterized by unstable G-quadruplex activity.
Assignments (2)
CONFIRMATORY LICENSE
Recorded Dec 6, 2023
From: UNIVERSITY OF ARIZONA
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065791/0804 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 10, 2022
From: HURLEY, LAURENCE; DE, BISWANATH; CHAPPETA, VENKATESHWAR R.; BROOKS, TRACY A.; GOKHALE, VIJAY; MIRANTI, CYNTHIA; REYES REYES, ELSA
To: ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA
Reel/Frame 061131/0406 →
Continuity (2)
Provisional Application
62798293
· Jan 29, 2019
References Cited (60)
US 3989816A
· Rajadhyaksha
· 1976
[cited by applicant]
US 4444762A
· Rajadhyaksha
· 1984
[cited by applicant]
US 5770581A
· Weichselbaum et al.
· 1998
[cited by applicant]
US 8158646B2
· Ablordeppy
· 2012
[cited by applicant]
US 20070249564A1
· Erion et al.
· 2007
[cited by applicant]
WO WO2007062998
· 2007
[cited by applicant]
Johnson et al. British Journal of Cancer 2001 84 10 1424 (Year: 2001).
[cited by examiner]
J. Figueiredo et al. Life Sciences, 340 (2024) 1222481 (Year: 2024).
[cited by examiner]
Y. H. Wang et. al. Nucleic Acids Research 2022 50 (Year: 2022).
[cited by examiner]
Gura et al. Science 278 5430 1997 1041 (Year: 1997).
[cited by examiner]
Kunnumakkara Experimental Biology and Medicine 2019 244 663 (Year: 2019).
[cited by examiner]
Cannon et. al. Burgers Medicinal Chemistry and Drug Discovery 5th ed. 1995 (Year: 1995).
[cited by examiner]
Frasson et. al. “Quindoline-derivatives display potent G-quadruplex-mediated antiviral activity against herpes simplex virus 1” Antiviral Research 2022, 208, 105432, 1-9 DOI: 10.1016/j.antiviral.2022.105432 (Year: 2022).
[cited by examiner]
Haider et. al. “Intramolecular [4+2] cycloaddition reactions of indolylalkylpyridazines: synthesis of annulated carbazoles” Tetrahedron, 2004, 60, 31, 6495-6507. DOI: 10.1016/j.tet.2004.06.008 (Year: 2004).
[cited by examiner]
Indumathi et. al. “Novel synthesis of benzo[b]carbazoles” Tetrahedron Letters, 2014, 55, 5361-5364. DOI: 10.1016/j.tetlet.2014.07.070 (Year: 2014).
[cited by examiner]
Yamamoto, M., Mine, H., Akazawa, K., Maehara, Y., & Sugimachi, K. “Gastrointestinal cancer and herpes zoster in adults.” Hepato-gastroenterology, 2003, 50, 52, abstract only. PMID: 12845977. Accessed Jan. 23, 2025. (Yea…
[cited by examiner]
International Search Report and Written Opinion for PCT/US20/15717. Mailed Jun. 11, 2020. 12 pages.
[cited by applicant]
Artusi et al., The Herpes Simplex Virus-1 genome contains multiple clusters of repeated G-quadruplex: Implications for the antiviral activity of a G-quadruplex ligand. Antiviral Res. Jun. 2015;118:123-31.
[cited by applicant]
Bierer et al., Antihyperglycemic activities of cryptolepine analogues: an ethnobotanical lead structure isolated from Cryptolepis sanguinolenta. J Med Chem. Jul. 16, 1998;41(15):2754-64.
[cited by applicant]
Bundgard, Design of Prodrugs. Elsevier, Amsterdam 1985. TOC only. 2 pages.
[cited by applicant]
Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995. pp. 949-982.
[cited by applicant]
Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995. pp. 172-178.
[cited by applicant]
Callegaro et al., A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication. Sci Rep. May 24, 2017;7(1):2341. 9 pages.
[cited by applicant]
Che et al., Discovery of Novel Schizocommunin Derivatives as Telomeric G-Quadruplex Ligands That Trigger Telomere Dysfunction and the Deoxyribonucleic Acid (DNA) Damage Response. J Med Chem. Apr. 26, 2018;61(8):3436-345…
[cited by applicant]
Daelemans et al., A time-of-drug addition approach to target identification of antiviral compounds. Nat Protoc. Jun. 2011;6(6):925-33.
[cited by applicant]
De Armond et al., Evidence for the presence of a guanine quadruplex forming region within a polypurine tract of the hypoxia inducible factor 1alpha promoter. Biochemistry. Dec. 13, 2005;44(49):16341-50.
[cited by applicant]
De Feo et al., Rat carotid arteriotomy: c-myc is involved in negative remodelling and apoptosis. J Cardiovasc Med (Hagerstown). Jan. 2006;7(1):61-7.
[cited by applicant]
Dexheimer et al., Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. J Am Chem Soc. Apr. 26, 2006;128(16):5404-15.
[cited by applicant]
Elion. Acyclovir: discovery, mechanism of action, and selectivity. J Med Virol. 1993;Suppl 1:2-6.
[cited by applicant]
Hahn et al., Modulation of gene expression by high and low density lipoproteins in human vascular smooth muscle cells. Biochem Biophys Res Commun. Aug. 15, 1991;178(3):1465-71.
[cited by applicant]
Hardin et al., Monovalent cation induced structural transitions in telomeric DNAs: G-DNA folding intermediates. Biochemistry. May 7, 1991;30(18):4460-72.
[cited by applicant]
He et al., New quinazoline derivatives for telomeric G-quadruplex DNA: effects of an added phenyl group on quadruplex binding ability. Eur J Med Chem. May 2013;63:1-13.
[cited by applicant]
Higuchi ed et al., Pro-Drugs as Novel Delivery Systems. Am. Chem. Soc., 1975. TOC only. 13 pages.
[cited by applicant]
Hurley et al., Modulating the functional contributions of c-Myc to the human endothelial cell cyclic strain response. J Vasc Res. 2010;47(1):80-90.
[cited by applicant]
Johnston et al., Synthesis of potential anticancer agents. 38. N-Nitrosoureas. 4. Further synthesis and evaluation of haloethyl derivatives. J Med Chem. Jul. 1971;14(17):600-14.
[cited by applicant]
Kipshidze et al., Antisense therapy for restenosis following percutaneous coronary intervention. Expert Opin Biol Ther. Jan. 2005;5(1):79-89.
[cited by applicant]
Komuro et al., Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett. Oct. 10, 1988;238(2):249-52.
[cited by applicant]
Le Sann et al., Synthesis and preliminary evaluation of novel analogues of quindolines as potential stabilisers of telomeric G-quadruplex DNA. Tetrahedron 2007, vol. 63, Iss 52. 12903-12911.
[cited by applicant]
Marin et al., Distribution of c-myc oncoprotein in healthy and atherosclerotic human carotid arteries. J Vasc Surg. Aug. 1993;18(2):170-6.
[cited by applicant]
Meyer et al., Reflecting on 25 years with MYC. Nat Rev Cancer. Dec. 2008;8(12):976-90.
[cited by applicant]
Miyazaki et al., Rational design of 4-amino-5,6-diaryl-furo[2,3-d] pyrimidines as potent glycogen synthase kinase-3 inhibitors. Bioorg Med Chem Lett. Mar. 15, 2008;18(6):1967-71.
[cited by applicant]
Naftilan et al., Angiotensin II induces c-fos expression in smooth muscle via transcriptional control. Hypertension. Jun. 1989;13(6 Pt 2):706-11.
[cited by applicant]
Ou et al., Stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc by quindoline derivatives. J Med Chem. Apr. 5, 2007;50(7):1465-74.
[cited by applicant]
Palumbo et al., Formation of a Unique End-to-End Stacked Pair of G-Quadruplexes in the hTERT Core Promoter with Implications for Inhibition of Telomerase by G-Quadruplex-Interactive Ligands. J. Am. Chem. Soc. 2009, 131,…
[cited by applicant]
Qin et al., Characterization of the G-quadruplexes in the duplex nuclease hypersensitive element of the PDGF-A promoter and modulation of PDGF-A promoter activity by TMPyP4. Nucleic Acids Res. 2007;35(22):7698-713.
[cited by applicant]
Qin et al., Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regions. Biochimie. Aug. 2008;90(8):1149-71.
[cited by applicant]
Ragazzon et al., Competition dialysis: a method for the study of structural selective nucleic acid binding. Methods. Jun. 2007;42(2):173-82.
[cited by applicant]
Shachaf et al., Genomic and proteomic analysis reveals a threshold level of MYC required for tumor maintenance. Cancer Res. Jul. 1, 2008;68(13):5132-42.
[cited by applicant]
Shi et al., Downregulation of c-myc expression by antisense oligonucleotides inhibits proliferation of human smooth muscle cells. Circulation. Sep. 1993;88(3):1190-5.
[cited by applicant]
Siddiqui-Jain et al., Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc Natl Acad Sci U S A. Sep. 3, 2002;99(18):11593-8.
[cited by applicant]
Silverman, The Organic Chemistry of Drug Design and Drug Action, Academic Press, San Diego, CA 1992. pp. 352-401.
[cited by applicant]
Sun et al., Facilitation of a structural transition in the polypurine/polypyrimidine tract within the proximal promoter region of the human VEGF gene by the presence of potassium and G-quadruplex-interactive agents. Nuc…
[cited by applicant]
Takeuchi et al., Synthesis and antitumor activity of fused quinoline derivatives. V. Methylindolo[3,2-b] quinolines. Chem Pharm Bull (Tokyo). Dec. 1997;45(12):2096-9.
[cited by applicant]
Van Oeveren et al., Discovery of an androgen receptor modulator pharmacophore based on 2-quinolinones. Bioorg Med Chem Lett. Mar. 15, 2007;17(6):1523-6.
[cited by applicant]
Verma et al., Genome-wide computational and expression analyses reveal G-quadruplex DNA motifs as conserved cis-regulatory elements in human and related species. J Med Chem. Sep. 25, 2008;51(18):5641-9.
[cited by applicant]
Von Rahden et al., c-myc amplification is frequent in esophageal adenocarcinoma and correlated with the upregulation of VEGF-A expression. Neoplasia. Sep. 2006;8(9):702-7.
[cited by applicant]
Weiss et al., Dissociation between activation of growth-related genes and mitogenic responses of neonatal vascular smooth muscle cells. Biochem Biophys Res Commun. Dec. 16, 1991;181(2):617-22.
[cited by applicant]
Xiang et al., Piperazine sulfonamides as potent, selective, and orally available 11beta-hydroxysteroid dehydrogenase type 1 inhibitors with efficacy in the rat cortisone-induced hyperinsulinemia model. J Med Chem. Jul. …
[cited by applicant]
Yuan et al., Mass spectrometry of G-quadruplex DNA: formation, recognition, property, conversion, and conformation. Mass Spectrom Rev. Nov.-Dec. 2011;30(6):1121-42.
[cited by applicant]