Syntheses and evaluation of multicaulin and miltirone-like compounds as antituberculosis agents

Burmaoğlu, Serdar; Seçinti, Hatice; Mozioğlu, Erkan; Gören, Ahmet; Altundaş, Ramazan; Seçen, Hasan

doi:10.1080/14756366.2017.1337758

Cited by 4 publications

(2 citation statements)

References 24 publications

(20 reference statements)

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“…One underused family of cytotoxic natural products is the ortho -quinones. Several low-molecular-weight compounds that contain an ortho -quinone group, such as β-lapachone 8 , tanshinones (I, IIA, IIB and crypto) 9 , mansonones A–G 10 , dunnione 11 , miltirone 12 , salvicine 13 and caryopteron A 14 , display wide antiproliferative effects in vitro. For example, β-lapachone ( 1 , Fig.…”

Section: Mainmentioning

confidence: 99%

Controlled masking and targeted release of redox-cycling ortho-quinones via a C–C bond-cleaving 1,6-elimination

et al. 2022

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Natural products that contain ortho-quinones show great potential as anticancer agents but have been largely discarded from clinical development because their redox-cycling behaviour results in general systemic toxicity. Here we report conjugation of ortho-quinones to a carrier, which simultaneously masks their underlying redox activity. C-benzylation at a quinone carbonyl forms a redox-inactive benzyl ketol. Upon a specific enzymatic trigger, an acid-promoted, self-immolative C–C bond-cleaving 1,6-elimination mechanism releases the redox-active hydroquinone inside cells. By using a 5-lipoxygenase modulator, β-lapachone, we created cathepsin-B-cleavable quinone prodrugs. We applied the strategy for intracellular release of β-lapachone upon antibody-mediated delivery. Conjugation of protected β-lapachone to Gem-IgG1 antibodies, which contain the variable region of gemtuzumab, results in homogeneous, systemically non-toxic and conditionally stable CD33+-specific antibody–drug conjugates with in vivo efficacy against a xenograft murine model of acute myeloid leukaemia. This protection strategy could allow the use of previously overlooked natural products as anticancer agents, thus extending the range of drugs available for next-generation targeted therapeutics.

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Section: Mainmentioning

confidence: 99%

Controlled masking and targeted release of redox-cycling ortho-quinones via a C–C bond-cleaving 1,6-elimination

et al. 2022

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“…Another approach is that miltirone and bidwillon A, as prototypes of natural origin, should be used for chemical modification and structure–activity relationship (SAR) studies to improve its P-gp-inhibiting properties and to drive forward the development of clinical candidates. Miltirone derivatives have been synthesized in the past and subjected to SAR studies in different contexts [ 75 , 76 , 77 ]. These studies may be taken as a proof-of-principle that at least miltirone is in general suitable for derivatization and SAR studies.…”

Section: Discussionmentioning

confidence: 99%

In Silico and In Vitro Identification of P-Glycoprotein Inhibitors from a Library of 375 Phytochemicals

Schäfer,

Klösgen,

Omer

et al. 2023

IJMS

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Cancer therapy with clinically established anticancer drugs is frequently hampered by the development of drug resistance of tumors and severe side effects in normal organs and tissues. The demand for powerful, but less toxic, drugs is high. Phytochemicals represent an important reservoir for drug development and frequently exert less toxicity than synthetic drugs. Bioinformatics can accelerate and simplify the highly complex, time-consuming, and expensive drug development process. Here, we analyzed 375 phytochemicals using virtual screenings, molecular docking, and in silico toxicity predictions. Based on these in silico studies, six candidate compounds were further investigated in vitro. Resazurin assays were performed to determine the growth-inhibitory effects towards wild-type CCRF-CEM leukemia cells and their multidrug-resistant, P-glycoprotein (P-gp)-overexpressing subline, CEM/ADR5000. Flow cytometry was used to measure the potential to measure P-gp-mediated doxorubicin transport. Bidwillon A, neobavaisoflavone, coptisine, and z-guggulsterone all showed growth-inhibitory effects and moderate P-gp inhibition, whereas miltirone and chamazulene strongly inhibited tumor cell growth and strongly increased intracellular doxorubicin uptake. Bidwillon A and miltirone were selected for molecular docking to wildtype and mutated P-gp forms in closed and open conformations. The P-gp homology models harbored clinically relevant mutations, i.e., six single missense mutations (F336Y, A718C, Q725A, F728A, M949C, Y953C), three double mutations (Y310A-F728A; F343C-V982C; Y953A-F978A), or one quadruple mutation (Y307C-F728A-Y953A-F978A). The mutants did not show major differences in binding energies compared to wildtypes. Closed P-gp forms generally showed higher binding affinities than open ones. Closed conformations might stabilize the binding, thereby leading to higher binding affinities, while open conformations may favor the release of compounds into the extracellular space. In conclusion, this study described the capability of selected phytochemicals to overcome multidrug resistance.

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Recent Progress on the Identification of Phenanthrene Derivatives in Traditional Chinese Medicine and Their Biological Activities

Feng

Dai

et al. 2022

Pharmacological Research - Modern Chinese Medicine

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Syntheses and evaluation of multicaulin and miltirone-like compounds as antituberculosis agents

Cited by 4 publications

References 24 publications

Controlled masking and targeted release of redox-cycling ortho-quinones via a C–C bond-cleaving 1,6-elimination

Controlled masking and targeted release of redox-cycling ortho-quinones via a C–C bond-cleaving 1,6-elimination

In Silico and In Vitro Identification of P-Glycoprotein Inhibitors from a Library of 375 Phytochemicals

Recent Progress on the Identification of Phenanthrene Derivatives in Traditional Chinese Medicine and Their Biological Activities

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