Cephalostatin 1 analogues activate apoptosis via the endoplasmic reticulum stress signaling pathway

Tahtamouni, Lubna H.; Nawasreh, Mansour; Al-Mazaydeh, Zainab A.; Al-Khateeb, Rema A.; Abdellatif, Reem N.; Bawadi, Randa; Bamburg, James R.; Yasin, Salem R.

doi:10.1016/j.ejphar.2017.11.025

Cited by 18 publications

(17 citation statements)

References 41 publications

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“…These metabolites show a unique cytotoxicity profile in in vitro screenings that were conducted at the National Cancer Institute. Indeed, cephalostatin 1 is an extremely powerful agent that acts via a unique apoptosis pathway [5] which was also found by us or an analogue [6]. The first total synthesis of cephalostatin 1 1 and several other natural analogues from the same family were reported by Fuchs et al [7] Later, Shair and coworkers disclosed the second total synthesis of cephalostatin 1 1 [8].…”

Section: Introductionmentioning

confidence: 67%

Novel double functional protection of cephalostatin analogues using a gas-free chlorination method

Nawasreh

Kirschning

Duddeck

et al. 2020

Heliyon

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Herewith, we report on a method that allows to simultaneously protect both the Δ 14,15 bond and the carbonyl group of the symmetrical bis-steroidal diketone 2. We found that environmentally friendly and gas-free chlorination is ideally suited to achieve this goal. This method was discovered during our efforts to methoxylate 2 in a solution of dichloromethane and basic methanol in the presence of diacetoxy iodobenzene. Unexpectedly, the Δ 14,15 bonds were chlorinated once as well as twice in a statistical manner. Interestingly, the singly dichlorinated desymmetrized product is an ideal precursor for conduction a series of position selective transformations. Importantly, the carbonyl group present in the nonchlorinated hemisphere can be selectively reduced, olefinated or oximated, while the other carbonyl group stays unaltered. A structurally related "monomeric" steroid derivative undergoes Δ 14,15 chlorination and 11-position methoxylation under same conditions. These findings represent a powerful entry for preparing new nonsymmetrical cephalostatin derivatives.

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Section: Introductionmentioning

confidence: 67%

Novel double functional protection of cephalostatin analogues using a gas-free chlorination method

Nawasreh

Kirschning

Duddeck

et al. 2020

Heliyon

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“…The cytotoxicity of these compounds against four selected cancer cell lines is summarized in Table 1. Interestingly, compound 5 has shown a powerful activity against three selected cell lines using the MTT assay [22] with low GI 50 values (10 −1 μM range). This may be rationalized based on the effect of 15α‐OH which may mimic the common functionality in the extremely active 17α‐hydroxylated cephalostatins.…”

Section: Resultsmentioning

confidence: 99%

Novel Epoxidation/Oxygenation Method toward Bioactive Cephalostatins Using Common Alkaline Metals

Nawasreh

2022

ChemistrySelect

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Cephalostatins (e. g. cephalostatin 1) are a class of natural products that exert extraordinary antitumor activity with the presence of a significant number of oxygen atoms either in etheric, alcoholic, or epoxydic form. Here, we describe a novel epoxidation method of ▵14,15 bond of the symmetrical bis‐steroidal pyrazine (BSP) (the diketone 2) using only grounded lithium metal in dry THF. This chemo and regioselective method which forms an environmentally begin solved one of the major challenges that overcome the N‐oxide formation in BSP's. The epoxidized products underwent a regioselective reduction with sodium borohydride NaBH4 yielding 15α‐hydroxy derivatives. Interestingly, the triol derivative 5 was found to exert a powerful activity against the three selected cancer cell lines: K562, MCF‐7, and DU‐145 using MTT assay (average GI50<0.1 μM). Noteworthy, the BSP 7 (with vicinal‐diol functionality) was obtained when the epoxidized derivatives 4 was treated with sodium metal in dry THF.

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“…The quantity of caspase 3, caspase 4, caspase 8, caspase 9 mRNA was determined by qRT-PCR (Tahtamouni et al 2018;Nawasreh et al 2020). Total RNA from vehicle-treated control and GI 50 -treated cells was extracted according to the manufacturer instructions (Total RNA Isolation System, Sigma-Aldrich, USA).…”

Section: Quantitative Reverse Transcription Polymerase Chain Reaction (Qrt-pcr)mentioning

confidence: 99%

A novel derivative of picolinic acid induces endoplasmic reticulum stress-mediated apoptosis in human non-small cell lung cancer cells: synthesis, docking study, and anticancer activity

Abbas¹,

Mahmood²,

Tahtamouni³

et al. 2021

PHAR

Self Cite

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Thirteen new derivatives of picolinic acid (4–7) were designed and synthesized from the starting parent molecule, picolinic acid. The new compounds were characterized by ATR-FTIR, 1HNMR, and CHNS analysis. A molecular docking study was performed to evaluate the binding affinity of the synthesized compounds toward EGFR kinase domain that indicated occupation of the critical site of EGFR kinase pocket and excellent positioning of the compounds in the pocket. The cytotoxic activity of the compounds against two human cancer cell lines (A549 and MCF-7), the non-tumorigenic MCF10A cell line, and white blood cells (WBC) was evaluated using the MTT assay. Compound 5 showed anticancer activity against A549 lung cancer cells (IC50 = 99.93 µM) but not against MCF-7 breast cancer cells or normal cells. Compound 5 mediated cytotoxicity in A549 lung cancer cells by inducing apoptotic cell death, as suggested by fragmented nuclei after DAPI staining, and agarose gel electrophoresis. Moreover, compound 5 triggered the activation of caspases 3, 4 and 9. However, compound 5 treatment did not affect the release of cytochrome c from the mitochondria to the cytosol, as compared to the vehicle-treated control cells. Nevertheless, compound 5-treated cells reported greater release of smac/DIABLO to the cytosol. In the same context, both compound 5 and thapsigargin (specific inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)) enhanced eIF2 phosphorylation, reflecting the activation of the atypical ER stress pathway and the potential applicability of compound 5 in lung cancer treatment.

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Cephalostatin 1 analogues activate apoptosis via the endoplasmic reticulum stress signaling pathway

Cited by 18 publications

References 41 publications

Novel double functional protection of cephalostatin analogues using a gas-free chlorination method

Novel double functional protection of cephalostatin analogues using a gas-free chlorination method

Novel Epoxidation/Oxygenation Method toward Bioactive Cephalostatins Using Common Alkaline Metals

A novel derivative of picolinic acid induces endoplasmic reticulum stress-mediated apoptosis in human non-small cell lung cancer cells: synthesis, docking study, and anticancer activity

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