April 2024
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33 Reads
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6 Citations
Journal of Medicinal Chemistry
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April 2024
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33 Reads
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6 Citations
Journal of Medicinal Chemistry
March 2024
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7 Reads
Cancer Research
MYC is one of the most validated driver oncogenes and is overexpressed in most human cancers. However, the MYC protein is considered “undruggable” due to its disordered structure and difficulties associated with targeting transcription factors. The MYC gene promoter forms G- quadruplex, a four-stranded non-canonical DNA secondary structure. The MYC G-quadruplex functions as a transcription silencer and further inhibits MYC expression upon drug binding, representing an exciting approach for MYC-targeting cancer therapy. Indenoisoquinolines are topoisomerase I inhibitors with better physicochemical and biological properties than the clinical camptothecin drugs. We previously revealed a novel mechanism of action for active anticancer indenoisoquinolines by dual inhibition of MYC and topoisomerase I, where potent MYC inhibition was achieved through targeting its promoter G-quadruplex. Herein, we report the design, cellular activity, and in vivo efficacy of novel anticancer 7-aza-8,9-methylenedioxyindenoisoquinoline derivatives based on optimized substituents and π-π stacking interactions. Using biophysical, biochemical, and cellular assays, we demonstrated that the new indenoisoquinoline derivatives greatly stabilized the MYC promoter G-quadruplex, significantly lowered MYC protein and mRNA levels in cancer cells, and inhibited topoisomerase I activity. A MYC G-quadruplex mediated mechanism of action was evident by differential activities in Raji vs CA-46 cells. The importance of MYC targeting was corroborated by potent cytotoxicity against a panel of MYC-dependent cancer cell lines as well as the NCI-60 panel of human cancer cell lines. The top three candidates were evaluated for pharmacokinetics and in vivo anticancer properties. Excellent metabolic stability, bioavailability, and tumor accumulation were observed in xenograft mouse models. Potent and significant tumor growth inhibition was demonstrated in the aggressive RD-ES Ewing Sarcoma xenograft mouse model while the drugs were well-tolerated. In addition, favorable brain penetration and pharmacokinetics were established, which encourage future evaluations in difficult-to-treat brain tumors. In conclusion, we designed and developed 7-aza-8,9-methylenedioxyindenoisoquinoline derivatives that are dual inhibitors of MYC and topoisomerase I. Our drug candidates demonstrated excellent pharmacokinetics and in vivo anticancer activities with promising indications in MYC-dependent cancers. Citation Format: Yichen Han, Luying Chen, Adam Buric, Venkat Chintareddy, Pooran Chand, Randall Riggs, Mark Cushman, Danzhou Yang. Design and anticancer biological evaluation of novel 7-aza-8,9-methylenedioxyindenoisoquinoline derivatives that inhibit MYC and topoisomerase I [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5964.
April 2023
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38 Reads
Cancer Research
MYC is one of the most important oncogenes and is overexpressed in a number of human cancers. The G-quadruplex formed in the MYC oncogene promoter (MycG4) is a transcriptional silencer and amenable to small molecule targeting. G-quadruplexes are noncanonical four-stranded DNA or RNA secondary structures that have emerged as novel therapeutic targets. Indenoisoquinolines are human topoisomerase I inhibitors with improved physicochemical and biological properties as compared to the clinically used camptothecin anticancer drugs. Three indenoisoquinolines, indotecan (LMP400), indimitecan (LMP776), and LMP744, have entered phase I clinical trials in adults with relapsed solid tumors and lymphomas. However, some indenoisoquinolines showed potent anticancer activity without being strong topoisomerase I inhibitors, suggesting additional mechanisms of action. Herein, we demonstrate that a large number of anticancer indenoisoquinolines strongly bind and stabilize MycG4 in vitro, using fluorescence, nuclear magnetic resonance (NMR), and circular dichroism (CD) spectroscopy, as well as gel electromobility shift assay (EMSA). In addition, MycG4-interactive indenoisoquinolines lower MYC mRNA and protein levels in vivo, as shown by western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) experiments. Structure-activity-relationships of MycG4 recognition by indenoisoquinolines were investigated to understand structural requirements for binding. Systemic analysis of indenoisoquinoline derivatives led to the discovery of a synergistic effect of MYC inhibition and topoisomerase I inhibition on anticancer activity. Therefore, these results indicate that targeting the MYC promoter G-quadruplex to downregulate MYC is a new mechanism of action for anticancer indenoisoquinolines. Moreover, our data reveals dual targeting of MycG4 and topoisomerase I as a novel strategy for cancer therapy. Citation Format: Danzhou Yang, Mark Cushman, Kai-Bo Wang, Mohamed S. Elsayed, Guanhui Wu, Adam J. Buric, Mercedes DeMoss. Dual targeting MYC G-quadruplex and topoisomerase I by indenoisoquinolines for cancer therapy [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 3103.
April 2022
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24 Reads
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5 Citations
Bioorganic & Medicinal Chemistry Letters
Resistance to telithromycin and off-target effects associated with the metabolic instability present serious and challenging problems for the development of novel macrolides. Herein, studies of hybrids of macrolides and quinolones (termed macrolones) bridged with linkers from 11,12-cyclic carbamate of macrolides revealed different structure-activity relationships from the previously reported macrolones bridged with linkers derived from 6-, 9- and 4''-positions of macrolides. The optimized macrolone 34g with a longer and rigid sidechain than telithromycin had improved metabolic stability compared to telithromycin (t1/2: 110 vs 32 min), whose future has been heavily clouded by metabolic issues. Moreover, 34g was 38-fold more potent than telithromycin against A2058/2059-mutated Mycoplasma pneumoniae (8 vs 315 μM), which may be attributed to a novel mode of action between the carboxylic acid of quinolone moiety and the bacterial ribosome. This work increases the prospect for discovery of novel and safe antibacterial agents to combat serious human infectious diseases.
March 2020
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49 Reads
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23 Citations
European Journal of Medicinal Chemistry
In the search for novel hybrid molecules by fusing two biologically active scaffolds into one heteromeric chemotype, we found that hybrids of azithromycin and ciprofloxacin/gatifloxacin 26j and 26l can inhibit the supercoiling activity of E. coli gyrase by poisoning it in a way similar to fluoroquinolones. This may modestly contribute to their potencies, which are equal to ciprofloxacin against constitutively resistant Staphylococcus aureus, whose growth is not inhibited by the presence of macrolides. In contrast, introduction of quinolines (the 3-quinoline 26b and the 6-quinoline 26o) with an optimized rigid spacer at the 6-OH of azithromycin acylides did not exert significant potency against constitutively resistant S. aureus, despite the fact that the quinoline-containing compounds, exemplified by 26o, were as active as telithromycin against susceptible, inducibly- and efflux-resistant pathogens. The novel dual modes of action involving protein synthesis inhibition and poisoning DNA replication may pave the way for restoration of antibacterial activities of the current macrolides against constitutively resistant clinical isolates.
November 2019
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244 Reads
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3 Citations
BMC Veterinary Research
Background: Canine leishmaniasis is a zoonotic disease caused by Leishmania infantum, being the dogs one of the major reservoirs of human visceral leishmaniasis. DNA topology is a consolidated target for drug discovery. In this regard, topoisomerase IB - one of the enzymes controlling DNA topology - has been poisoned by hundreds of compounds that increase DNA fragility and cell death. Aromathecins are novel molecules with a multiheterocyclic ring scaffold that have higher stability than camptothecins. Results: Aromathecins showed strong activity against both forms of L. infantum parasites, free-living promastigotes and intra-macrophagic amastigotes harbored in ex vivo splenic explant cultures obtained from infected BALB/c mice. However, they prevented the relaxation activity of leishmanial topoisomerase IB weakly, which suggests that the inhibition of topoisomerase IB partially explains the antileishmanial effect of these compounds. The effect of aromathecins was also studied against a strain resistant to camptothecin, and results suggested that the trafficking of these compounds is not through the ABCG6 transporter. Conclusions: Aromathecins are promising novel compounds against canine leishmaniasis that can circumvent potential resistances based on drug efflux pumps.
September 2019
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107 Reads
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7 Citations
International Journal for Parasitology Drugs and Drug Resistance
DNA topoisomerases are considered consolidated druggable targets against diseases produced by trypanosomatids. Several reports indicated that indenoisoquinolines, a family of non-camptothecinic based topoisomerase poisons, have a strong leishmanicidal effect both in vitro and in vivo in murine models of visceral leishmaniasis. The antileishmanial effect of the indenoisoquinolines implies several mechanisms that include the stabilization of the cleavage complex, histone H2A phosphorylation and DNA fragmentation. A series of 20 compounds with the indenoisoquinoline scaffold and several substituents at positions N6, C3, C8 and C9, were tested both in promastigotes and in intramacrophage splenic amastigotes obtained from an experimental murine infection. The antileishmanial effect of most of these compounds was within the micromolar or submicromolar range. In addition, the introduction of an N atom in the indenoisoquinoline ring (7-azaindenoisoquinolines) produced the highest selectivity index along with strong DNA topoisomerase IB inhibition, histone H2A phosphorylation and DNA-topoisomerase IB complex stabilization. This report shows for the first time the effect of a series of synthetic indenoisoquinolines on histone H2A phosphorylation, which represents a primary signal of double stranded DNA break in genus Leishmania.
June 2019
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270 Reads
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87 Citations
Journal of the American Chemical Society
March 2019
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37 Reads
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15 Citations
European Journal of Medicinal Chemistry
Constitutively erythromycin-resistant apathogens are more difficult to address than inducibly resistant and efflux-resistant strains. Three series of the 4th generation 2-fluoro 9-oxime erythromycin ketolides were synthesized and evaluated. Incorporation of substituted heteroaryl groups (a - m), in contrast to previously reported the unsubstituted heteroaryl groups, proved to the beneficial for enhancement of the activities of the 9-propgargyl ketolide 8 series and the 9-allyl ketolide 14 series. But these aryl groups (a - m) cannot supply the resulting compounds 8 and 14, unlike corresponding the 6-allyl ketolide 20 series, with activity against constitutively resistant Streptococcus pneumoniae. However, hybrids of macrolides and quinolones (8, 14 and 20, Ar = n - t) exhibited not only high activities against susceptible, inducibly erm-mediated resistant, and efflux-mediated resistant strains, but also significantly improved potencies against constitutively resistant Streptococcus pneumoniae and Streptococcus pyogenes. The capacity was highlighted by introduction of newly designed carbamoyl quinolones (q, r, s and t) rather than commonly seen carboxy quinolones (o and p) as the pharmacophores. Structure-activity relationships and molecular modelling indicated that 8r, 14r and 20q may have different binding sites compared to current erythromycins. Moreover, 8r, 14r and 20q have 2.5–3.6 times prolonged half-life and 2.3- to 2.6-fold longer mean residence time in vivo over telithromycin. These findings pave the way for rational design of novel non-telithromycin macrolides that target new binding sites within bacterial ribosomes.
March 2019
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28 Reads
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12 Citations
European Journal of Medicinal Chemistry
In general, potent non-ketolide versions of erythromycin possessed conformationally constricted two- or three-atom-length sidechains at 3-OH. Novel 14-membered non-ketolides possessing long spacers beyond three-atom length were evaluated for antibacterial activity. The most potent one is 34a, featuring a five-atom-length flexible linker from of a pyridine ring to the aglycone. Conversion of the pyridine of 34a to other aryl groups, changing the linker's length of 34a to longer or shorter ones, and variation of the linker flexibility to a rigid olefin or alkyne led to decreased antibacterial activity. The hybrids of macrolides and quinolones 28b, 31 and 34b possessing various sidechains, unlike their 15-membered counterparts, were ineffective compared to 34a. Similar to the marketed ketolide telithromycin, the non-ketolide 34a proved to be a time-dependent bactericidal agent, but it exhibited superior in vivo pharmacokinetic properties such as longer half-life, higher plasma concentration, lower clearance and shorter time to reach the highest drug concentration relative to telithromycin. Molecular docking suggested 34a might π - π interact with the bacterial ribosomal RNA base G2505Ec. This study suggested that the bacteriostatic agent erythromycin can be structurally modified to afford a new bactericidal chemotype that targets the ribosome and is superior to ciprofloxacin with regard to its minimum bactericidal concentration.
... This work has been followed (see for example references [34][35][36][37]) by very many studies in which a given promoter G4 has been targeted by a G4 ligand, with readouts of high G4 affinity and gene downregulation, most commonly from biophysical studies together with an in vitro expression assay. Sometimes expression changes are assessed in cellular experiments (see for example references [44,47,48,65,[102][103][104][105][106]). Popular target cancer-relevant genes include MYC, KRAS, c-KIT, BCL-2, and hTERT [34][35][36][37]. ...
April 2024
Journal of Medicinal Chemistry
... Because of the improved target engagement and avoidance of activation of inducible resistance genes, ketolides retained activity against many bacterial strains resistant to previous macrolides 38,39,42 . Unfortunately, toxicity issues curbed their medical use and stimulated a continuing search for newer derivatives 1,[4][5][6]44,45 . ...
April 2022
Bioorganic & Medicinal Chemistry Letters
... The resulting semisynthetic drugs greatly expanded the medical utility of several antibiotic classes 1,2 . However, while many of those efforts were based on ingenious chemical synthesis techniques, they were largely driven by the rather serendipitous generation of derivatives and establishing structure-activity relationships by microbiological testing [3][4][5][6][7][8] . Transition to knowledge-based approaches for antibiotic development requires a clear understanding of the mode of target engagement and mechanism of action of the new compounds. ...
March 2020
European Journal of Medicinal Chemistry
... This Th1-type response was related also to the induction of nitrite production by stimulated spleen cells of infected and treated animals, suggesting activation of host macrophages to kill the parasite. Others have likewise shown the development of similar immune profiles in response to treatment of Leishmania-infected mice with antileishmanial molecules, evidencing their relevance for the mammalian host to combat the infection [11,19,41]. ...
November 2019
BMC Veterinary Research
... This can result in accumulation of TOP1-bound nicks in the genome, which ultimately can lead to cell death by collision with the DNA replication and transcription machinery. Reduced TOP1 activity levels are detrimental for single-cell eukaryotes such as Trypanosoma brucei and L. major [22][23][24], while TOP1 appears only to be essential during early developmental stages in higher eukaryotes and mammals [25,26]. Hence, TOP1 inhibitors are of particular interest as potential antiparasitic drugs [10], while TOP1 poisons are of high interest as potential anti-cancer agents, since they convert TOP1 activity into a cell killer [27]. ...
September 2019
International Journal for Parasitology Drugs and Drug Resistance
... Employing molec-ular docking analysis, we explored the potential binding sites of compound 8 e with MycG4, utilizing the NMR (nuclear magnetic resonance) structure of the quindoline-MycG4 complex (2 : 1) obtained from the RCSB (research collaboratory for structural bioinformatics) Protein Data Bank (PDB code: 2L7V). [57,58] Our analysis revealed that the optimal docking poses of 8 e with MycG4 occurred at the 5'-and 3'-end G-quartets, with binding energies of À 6.6 kcal/mol and À 5.7 kcal/mol, respectively. Figure 10 illustrates the docking models of the 8 e-MycG4 complex, depicting similar binding models to the NMR-refined complex (2L7V). ...
June 2019
Journal of the American Chemical Society
... The MTB-encoded TlyA methyltransferase alters the 50S ribosomal subunit, impairing the interaction of capreomycin with its target [87]. MTB DNA methylation is one of the mechanisms associated with para-aminosalicylic acid resistance [88]. ...
March 2019
European Journal of Medicinal Chemistry
... Because of the improved target engagement and avoidance of activation of inducible resistance genes, ketolides retained activity against many bacterial strains resistant to previous macrolides 38,39,42 . Unfortunately, toxicity issues curbed their medical use and stimulated a continuing search for newer derivatives 1,[4][5][6]44,45 . ...
March 2019
European Journal of Medicinal Chemistry
... Antimetabolites disrupt the metabolic activities such as inhibiting essential enzymes and interfering RNA translation or transcription [9]. Topoisomerase inhibitors bind to enzymes essential for DNA replications [24,25]. These activities lead to DNA breaks, impaired enzymatic functions, and reduced RNA and protein productions, which eventually result in cell arrest and apoptosis. ...
December 2018
Oncotarget
... By proper planning, intramolecular cyclization can be performed, giving rise to different polycyclic 7-azaindoles. Compound I is obtained by a Buchwald-Hartwig amination and a C-H arylation in sequence or tandem [14], while II, a fused 7-membered azaindole, is made starting with a Sonogashira coupling and finalising with a palladium catalysed Scheme 1. Structure of the CSF1R inhibitor 1, the less active thienopyrimidine 2 and 7-azaindole analogue 3c. The initial retrosynthetic plan (in the frame) is shown with red wavy bonds indicating disconnections. ...
November 2018
Journal of Medicinal Chemistry