Archiv der Pharmazie

Design, synthesis, and biological evaluation of simplified tetrahydroisoquinoline analogs

AbstractA series of tetrahydroisoquinoline derivatives were prepared and their antitumor activity was studied against several human carcinoma cell lines, including Ketr3, BEL‐7402, BGC‐823, KB, HCT‐8, MCF‐7, HeLa, A2780, A549, and HT‐1080. Compound 20, an analog of phthalascidin 650, exhibited good broad‐spectrum antitumor activity in vitro. However, compounds 19 and 21, in which the side chains at C‐22 are simplified, showed no obvious antitumor activity, indicating that the C‐22 side chain of this type of compound has a greater impact on its activity. The difference in the in vivo activity between compound 20 and phthalascidin 650 also shows a significant effect of the substituents on the skeleton structure on the in vivo activity.

Loading of Dicarboxylatoplatinum(II)‐NHC Complexes in Bacterial Ghosts as an Advanced Development in Cancer Therapy

ABSTRACT This study aimed to improve the drug‐like properties of benzimidazole‐based Pt(II)‐N‐heterocyclic carbene (NHC) complexes, particularly by enhancing their water solubility and delivery to cancer cells. Accordingly, four new Pt(II) complexes of the benzimidazol‐2‐ylidene type, featuring monodentate carboxylato ligands, were prepared and their structures confirmed through a combination of spectroscopic and crystallographic techniques. Their stability in aqueous solution and cell culture medium was investigated by 1 H NMR spectroscopy and HPLC‐MS analysis. Cytotoxicity was assessed using the MTT assay in ovarian cancer cell lines (A2780wt (cisplatin sensitive) and A2780cis (cisplatin resistant)) and a noncancerous bone marrow stromal cell line (HS‐5). Most complexes exhibited cytotoxicity comparable to or exceeding that of carboplatin, with preferential activity toward cancer cells. Loading of all four Pt(II) complexes into bacterial ghost cells (BGs) derived from two different nonpathogenic bacterial strains, Escherichia coli (E. coli) Nissle 1917 and E. coli NM522 notably enhanced the intracellular accumulation and cytotoxicity. Furthermore, mechanistic studies demonstrated that all tested compounds, regardless of formulation, induced apoptosis. Their potential to trigger immunogenic cell death was also evaluated, though only a modest effect was observed on selected hallmarks. Collectively, these findings highlight the potential of dicarboxylatoplatinum(II)‐NHC complexes, particularly loaded into BG‐based formulations, as promising anticancer drug candidates.

New Sinomenine Derivative as a Potential Drug for Cervical Cancer via Inducing Ferroptosis

ABSTRACT Cervical cancer remains a serious threat to women's health due to chemotherapy resistance, poor prognosis, and survival rates. Novel anti‐cervical cancer agents are urgently needed. Sinomenine derivatives, which were prepared from sinomenine (a natural morphinane alkaloid), have been previously reported by us to be cytotoxic toward various cancer cell lines. Also, an increase in ROS production, which is associated with ferroptosis, was observed in cancer cells. In this study, we synthesized 18 sinomenine derivatives and evaluated their antitumor activity in vitro against four human tumor cell lines (HeLa, HepG2, A549, and HT‐29). Five derivatives ( 12 – 16 ) containing quinoline fragments showed broad‐spectrum antitumor activity. Significantly, 16 showed specific activity against HeLa and HT‐29 cells, with IC 50 values of 5.60 and 7.60 μM, respectively. Its optimal lipophilicity (−1 < log  P < 2) likely contributes to this efficacy. Further study in vitro showed that Derivative 16 could increase the accumulation of ferrous iron, which caused an increase in ROS levels and MDA contents, and a decrease in GPX4 activity. Western blot results showed that 16 decreased the FHTI‐to‐GAPDH, SLC7A11‐to‐GAPDH, and GPX4‐to‐GAPDH ratios. Molecular docking simulation results suggested that 16 can interact with ferroptosis‐related proteins via the van der Waals force, and cation–π, anion–π, and hydrogen bonding interactions. In brief, Compound 16 may be a potentially useful drug for the treatment of cervical cancer, as it induces ferroptosis in HeLa cells by inhibiting FTH1 expression and the SLC7A11/GSH/GPX4 pathway.

Isotretinoin as a Multifunctional Anticancer Agent: Molecular Mechanisms, Pharmacological Insights and Therapeutic Potential

ABSTRACT Despite notable advancements in conventional cancer therapies, challenges such as drug resistance, adverse effects, and high treatment costs remain significant obstacles. This situation calls for exploring new therapeutic options. One promising approach is drug repurposing, which uses existing medications with known effects to identify new anticancer agents. Isotretinoin (13‐ cis ‐retinoic acid), a vitamin A derivative typically used to treat severe acne, shows considerable potential as an anticancer agent. Recent studies suggest that isotretinoin has the potential to enhance the efficacy of cancer treatment and contribute to cancer inhibition by targeting specific molecular pathways. This review explores isotretinoin's chemistry, pharmacokinetics, and toxicity, emphasizing its role in cancer treatment through clinical and preclinical studies while elucidating its anticancer mechanisms. Both preclinical and clinical studies have revealed that isotretinoin can effectively inhibit the growth of tumor cells, induce apoptosis, and help regulate cellular differentiation in a range of cancers, including neuroblastoma, glioblastoma, breast, skin, lung, ovarian, cervical, and head and neck cancers. Isotretinoin works against cancer through several mechanisms. It activates retinoic acid receptors (RARs), suppresses oncogenic signaling pathways, and influences gene transcription related to cell cycle control and apoptosis. Moreover, combining isotretinoin with other treatments, like interferon‐alpha, chemotherapy drugs, or other targeted inhibitors, can create synergistic effects that improve treatment effectiveness and potentially lessen side effects. Although isotretinoin holds great promise, we still need more research to address its limitations, such as its toxicity, risks during pregnancy, and differing responses in various cancer types. Current research focuses on optimizing isotretinoin‐based therapies by refining dosage regimens to maximize efficacy and enhancing formulation strategies for improved absorption and reduced side effects. Ultimately, the use of isotretinoin in cancer treatment demonstrates the potential of repurposing established drugs and paves the way for more accessible and cost‐effective cancer therapies.

Emerging Coumestans in Cancer Therapy With Mechanistic Insights and Clinical Potential

ABSTRACT Coumestans are natural phytoestrogens with strong therapeutic potential for inhibiting hormone‐induced cancers, such as breast, ovarian, and prostate malignancies. They regulate many signaling pathways, including the PI3K/AKT, MAPK, NF‐κB, and JAK/STAT pathways. Challenges regarding the clinical application of coumestans include their poor bioavailability and distribution, rapid metabolic rate, low water solubility, and formulation. This review aims to provide a comprehensive overview of the anticancer mechanisms of a few important coumestan derivatives, namely coumestrol, wedelolactone, isofraxidin, and psoralidin. Methods for increasing the coumestan efficacy via synthetic biology, bioinformatics, and artificial intelligence are described in this review. To bridge the gap between bench to bedside, future directions should focus on emphasizing clinical validation and developing targeted delivery systems to understand the therapeutic potential of coumestans.

Synthesis and biological evaluation of salophen nickel(II) and cobalt(III) complexes as potential anticancer compounds

AbstractRecent in vitro investigations of N,N′‐bis(salicylidene)‐1,2‐phenylenediamine (SAP) iron(III) complexes substituted with alkyl (ethyl, propyl, butyl) carboxylates at position 4 in tumor and leukemia cells revealed strong cytotoxic activity. In continuation of this study, analogous nickel(II) and cobalt(III) complexes were synthesized and tested in HL‐60 leukemia, and cisplatin‐sensitive and ‐resistant A2780 ovarian cancer cell lines. The biological activity depended on the extent of cellular uptake and the formation of reactive oxygen species (ROS). Inactive [(Ni(II)SAP] complexes (1−3) only marginally accumulated in tumor cells and did not induce ROS. The cellular uptake of [Co(III)SAP]Cl complexes (4−6) into the cells depended on the length of the ester alkyl chain (ethyl, 4 < propyl, 5 < butyl, 6). The cytotoxicity correlated with the presence of ROS. The low cytotoxic complex 4 induced only few ROS, while 5 and 6 caused a good to outstanding antiproliferative activity, exerted high ROS generation, and induced cell death after 48 h. Necrostatin‐1 prevented the biological effects, proving necroptosis as part of the mode of action. Interestingly, the effects of 5 and 6 were not reversed by Ferrostatin‐1, but even enhanced upon simultaneous application to the tumor cells.

Targeting Ovarian Cancer With Pyrimidine Nucleobase and Nucleoside Analogs: Synthesis, In Vitro Cytotoxic Activity, and Molecular Docking

ABSTRACT Ovarian cancer remains one of the most lethal gynecological malignancies, underscoring the need for novel therapeutic strategies. In this study, a series of pyrimidine‐based nucleobase ( 7–14 ) and nucleoside ( 21–24 ) analogs were synthesized and evaluated for their potential anticancer activity through poly(ADP‐ribose) polymerase (PARP) inhibition. These compounds were tested for in vitro cytotoxicity on ovarian cancer cell lines OVCAR‐3 and KURAMOCHI. Among the synthesized derivatives—namely, 4‐(4‐substituted phenylamino)‐1‐cyclopentyl‐5‐( H /methyl)pyrimidine‐2(1 H )‐ones ( 7–14 ) and 4‐(4‐substituted phenylamino)‐1‐(β‐ d ‐ribofuranosyl)‐5‐methylpyrimidine‐2(1 H )‐ones ( 21–24 )—compound 8 exhibited the most potent cytotoxic activity. It significantly reduced cell viability in OVCAR‐3 (IC 50  = 27.1 ± 4.56 µM) and KURAMOCHI (IC 50  = 46.2 ± 4.87 µM) cells, outperforming the reference PARP inhibitor olaparib (IC 50  = 75.8 ± 6.1 µM for OVCAR‐3, IC 50  = 84.5 ± 11.4 µM for KURAMOCHI). These results suggest that compound 8 is a promising lead candidate for further development as an anticancer agent targeting PARP in ovarian cancer.

Evernic Acid: A Low‐Toxic and Selective Alternative to Chemotherapeutic Agents in the Treatment of Ovarian Cancer

ABSTRACTEvernic acid (EA) has emerged as a potential therapeutic agent with its low toxicity and anticancer properties. In this study, the anticancer effect of EA on ovarian cancer cell lines and normal ovarian surface epithelial cells (OSE) was evaluated. The antiproliferative effect of EA was evaluated by xCELLigence Real‐Time Cell analysis, colony formation assay, and acridine orange and DAPI staining methods. Genotoxicity analysis was performed by comet assay. The effect of EA on cell migration was analyzed by wound healing assay. The potential of EA to induce apoptosis was also determined by evaluating the changes in gene and protein expression levels by qRT‐PCR and Western blot analysis, respectively. EA was found to be a promising potential therapeutic agent for ovarian cancer without showing significant cytotoxic effect on normal cells. Furthermore, EA decreased the ability of ovarian cancer cells for migration, increased the rate of apoptosis by inhibiting BIRC5 and activating CASP3, triggered cell cycle arrest in the G2/M phase, and caused a decrease in mitochondrial membrane potential and genotoxic effects. The results have shown that EA could be an effective candidate molecule for ovarian cancer treatment.