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10 pages, 2453 KiB

Open AccessArticle

Targeting Carbohydrate Mimetics of Tetrahydrofuran-Containing Acetogenins to Prostate Cancer

by Patricia Gonzalez Periche, Jacky Lin, Naga V. S. D. K. Bhupathiraju, Teja Kalidindi, Delissa S. Johnson, Nagavarakishore Pillarsetty and David R. Mootoo

Molecules 2023, 28(7), 2884; https://doi.org/10.3390/molecules28072884 - 23 Mar 2023

Cited by 2 | Viewed by 2050

Abstract

The high potency of the tetrahydrofuran-containing acetogenins (THF-ACGs) against a broad range of human cancer cell lines has stimulated interest in structurally simpler mimetics. In this context, we have previously reported THF-ACG mimetics in which the THF and butenolide moieties of a mono-THF-ACG were replaced with carbohydrate and thiophene residues, respectively. In the present study, towards the targeting of these carbohydrate analogues to prostate cancer (PCa), we synthesized prodrugs in which a parent thiophene or butenolide congener was conjugated through a self-immolative linker to 2-[3-(1,3-dicarboxypropyl)ureido] pentanedioic acid (DUPA), a highly specific ligand for prostate-specific membrane antigen (PSMA), which is overexpressed on prostate tumors. Both prodrugs were found to be more active against receptor positive LNCaP than receptor-negative PC-3 cells, with 2.5 and 12 times greater selectivity for the more potent thiophene analog and the less active butenolide congener, respectively. This selectivity for LNCaP over PC-3 contrasted with the behavior of the parent drugs, which showed similar or significantly higher activity for PC-3 compared to LNCaP. These data support the notion that higher activity of these DUPA-derived prodrugs against LNCaP cells is connected to their binding to PSMA and suggest that the conjugation of PSMA ligands to this family of cytotoxic agents may be effective for targeting them to PCa. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Organic Compounds)

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21 pages, 11302 KiB

Open AccessArticle

Discovery of Ureido-Based Apcin Analogues as Cdc20-specific Inhibitors against Cancer

by Yiqin He, Xiangyang Le, Gaoyun Hu, Qianbin Li and Zhuo Chen

Pharmaceuticals 2023, 16(2), 304; https://doi.org/10.3390/ph16020304 - 15 Feb 2023

Cited by 3 | Viewed by 3023

Abstract

Cdc20 is a promising drug target that plays an important role in the mid-anaphase process of cellular mitosis, and Apcin is the only reported core structure of the Cdc20-specific inhibitor. Some potent Apcin derivatives were obtained in our previous research, and a structure–activity relationship was determined. In this study, we designed and synthesized a series of ureido-based Apcin derivatives. The proliferation-inhibition experiments on four cancer-cell lines showed that ureido skeleton could promote the anti-proliferation activity of purine-substituted compounds, whereas the ureido analogues with pyrimidine substitutes showed no significant improvement in the inhibitory effect compared with the original ones. Further tests confirmed that ureido-based compounds can enhance the binding affinity to Cdc20 by increasing the levels of Cdc20 downstream proteins. Compound 27 revealed a remarkably antitumor activity pattern against Hela (IC₅₀ = 0.06 ± 0.02 μM) and potent binding affinity to Cdc20. Moreover, compound 20 induced caspase-dependent apoptosis and cell-cycle arrest at the G2/M phase, and compound 27 induced caspase-dependent apoptosis and promoted microtubule polymerization. Finally, a molecular-docking simulation was performed for compounds 20 and 27 to predict the potential ligand–protein interactions with the active sites of the Cdc20 proteins. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs)

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15 pages, 693 KiB

Open AccessArticle

Synthesis of Sulfonamides Incorporating Piperidinyl-Hydrazidoureido and Piperidinyl-Hydrazidothioureido Moieties and Their Carbonic Anhydrase I, II, IX and XII Inhibitory Activity

by Davide Moi, Alessandro Deplano, Andrea Angeli, Gianfranco Balboni, Claudiu T. Supuran and Valentina Onnis

Molecules 2022, 27(17), 5370; https://doi.org/10.3390/molecules27175370 - 23 Aug 2022

Cited by 5 | Viewed by 2457

Abstract

Here we report a small library of hydrazinocarbonyl-ureido and thioureido benzenesulfonamide derivatives, designed and synthesized as potent and selective human carbonic anhydrase inhibitors (hCAIs). The synthesized compounds were evaluated against isoforms hCA I, II, IX and XII using acetazolamide (AAZ) as standard inhibitor. Several urea and thiourea derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The thiourea derivatives showed enhanced potency as compared to urea analogues. Additionally, eight compounds 5g, 5m, 5o, 5q, 6l, 6j, 6o and 6u were selected for docking analysis on isoform I, II, IX, XII to illustrate the potential interaction with the enzyme to better understand the activity against the different isoforms. Full article

(This article belongs to the Special Issue Research of Organic Chemicals for Biological Applications)

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11 pages, 2342 KiB

Open AccessArticle

Synthesis and In Vitro Antiproliferative Activity of 11-Substituted Neocryptolepines with a Branched ω-Aminoalkylamino Chain

by Elkhabiry Shaban, Marta Świtalska, Li Wang, Ning Wang, Fan Xiu, Ikuya Hayashi, Tran Anh Ngoc, Sachie Nagae, Samah El-Ghlban, Shiho Shimoda, Ahmed Abdel Aleem El Gokha, Ibrahim El Tantawy El Sayed, Joanna Wietrzyk and Tsutomu Inokuchi

Molecules 2017, 22(11), 1954; https://doi.org/10.3390/molecules22111954 - 12 Nov 2017

Cited by 10 | Viewed by 4912

Abstract

Neocryptolepine, which is a kind of tetracyclic indoloquinoline alkaloid, exhibits the inhibition of topoisomerase II and shows antiproliferative activity. The present study describes the synthesis and antiproliferative evaluation of several neocryptolepine analogues carrying a branched, functionalized dibasic side chain at C11. These 2-substituted 5-methyl-indolo[2,3-b]quinoline derivatives were prepared by nucleophilic aromatic substitution (S_NAr) of 11-chloroneocryptolepines with appropriate 1,2- and 1,3-diamines. Some of the 11-(ω-aminoalkylamino) derivatives were further transformed into 11-ureido and thioureido analogues. Many of the prepared neocryptolepine derivatives showed submicromolar antiproliferative activity against the human leukemia MV4-11 cell line. Among them, 11-(3-amino-2-hydroxy)propylamino derivatives 2h and 2k were the most cytotoxic with a mean IC₅₀ value of 0.042 μM and 0.057 μM against the MV4-11 cell line, 0.197 μM and 0.1988 μM against the A549 cell line, and 0.138 μM and 0.117 μM against the BALB/3T3 cell line, respectively. Full article

(This article belongs to the Collection Efficient Pharmaceutical and Chemical Approaches for Anticancer Therapy: Design, Preliminary Evaluations, and Further Developments)

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21 pages, 964 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Novel Urea- and Guanidine-Based Derivatives for the Treatment of Obesity-Related Hepatic Steatosis

by Xiaolin Liang, Heying Pei, Liang Ma, Yan Ran, Jinying Chen, Guangcheng Wang and Lijuan Chen

Molecules 2014, 19(5), 6163-6183; https://doi.org/10.3390/molecules19056163 - 15 May 2014

Cited by 11 | Viewed by 7756

Abstract

Leptin, the product of the obese gene, is an adipocyte-secreted protein hormone playing a key role in the progression of obesity and hepatic steatosis. In this study, 28 novel (thio)urea and guanidine-based analogues have been synthesized and N-(1-(4-(3-(2-chloroethyl)ureido)benzyl)piperidin-4-yl)-3-(trifluoromethyl) benzamide (7i) was found to be a potent regulator of leptin expression in 3T3-L1 adipocytes. Treatment with 7i at a dose of 50 mg/kg/day for 35 days reduced the body weight and liver weight of diet-induced obesity mice by 13.5% and 18.4%, respectively, while also improving the serum levels of triglyceride, total cholesterol, leptin, adiponectin, LDL-c, HDL-c. Hematoxylin-eosin (H&E) and Oil Red O staining also confirmed that 7i ameliorated fat deposition in liver tissue and restricted the size of adipocytes in obesity-related fatty liver disease. Full article

(This article belongs to the Section Medicinal Chemistry)

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