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Small Molecule Drug Design and Research: 3rd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 20 September 2025 | Viewed by 3290

Special Issue Editor


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Guest Editor
Department of Cellular Biology & Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
Interests: organic chemistry; medicinal chemistry; small molecules; drug-like compounds; tethered and fused diazacyclic compounds; heterocyclic peptidomimetics; combinatorial chemistry; solid phase organic synthesis
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Small Molecule Drug Design and Research”.

The last two decades have witnessed major breakthroughs in the identification of genes, gene products, metabolic pathways, and signaling pathways, as well as progress in miniaturization and robotics, enabling the development of high-throughput mechanism-based biological assays. How does one approach the challenge of generating diverse small-molecule libraries that are likely to provide robust hits against a wide variety of molecular targets and, at the same time, are sound platforms for rapid optimization, affording potent and selective chemical probes that reside within a novel and biologically relevant chemical space? Since no single library can possibly occupy the entire universe of chemical space, there is a widespread agreement that increased access to chemical diversity is needed to target the whole biological space and thus increase the number of targets that are considered “druggable”. The search for new therapeutic entities can proceed along three principal paths of exploration: random walks, building on existing active structures, and using macromolecules as templates for molecular assembly.

Furthermore, there are several practical considerations involved in the efficient production of new entities designed to provide novel chemical probes. For example, the starting materials should be readily available and inexpensive; the synthetic steps must be straightforward, efficient, and reproducible on a multigram scale; and the intermediates and final target species must be readily purified, preferably resulting from clean, high-yielding reactions that require minimal purification.

Because of high attrition rates, especially during the clinical phases of drug development, more attention is needed in the early drug design process on selecting candidate drugs whose physicochemical properties are predicted to result in fewer complications during development and, hence, are more likely to lead to an approved, marketed drug. Techniques such as in vitro experiments complemented with computation methods are increasingly used in early drug discovery to select compounds with more favorable ADME and toxicological profiles.

Prof. Dr. Adel Nefzi
Guest Editor

Manuscript Submission Information

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Keywords

  • drug design
  • diversity-oriented synthesis
  • combinatorial chemistry
  • computationally guided synthesis
  • drug-like compounds
  • computer modeling techniques

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Research

26 pages, 6573 KiB  
Article
Semisynthesis and Antitumour Evaluation of Natural Derivatives from ent-Kaurene ent-15α-Angeloyloxykaur-l6-en-3β-ol Isolated from Distichoselinum tenuifolium
by Yass K. Yasser, Daniel Gil, Houda Zentar, María Jesús Durán-Peña, Belen Prados-Lopez, Jorge Juárez-Moreno, José Manuel Botubol-Ares, Ali Haidour, Juan Sainz, Antonio Fernández, Ramón Alvarez-Manzaneda, Rachid Chahboun and Fernando J. Reyes-Zurita
Int. J. Mol. Sci. 2024, 25(23), 13222; https://doi.org/10.3390/ijms252313222 - 9 Dec 2024
Viewed by 1183
Abstract
Two natural ent-kaurene diterpenoids, ent-15α-angeloyloxykaur-16-en-3β-ol (7) and ent-15α-angeloyloxykaur-16-en-3β,9-diol (8), were extracted from the aerial parts of Distichoselinum tenuifolium, and six new derivatives were synthesised from compound (7). The antitumour properties of these natural and [...] Read more.
Two natural ent-kaurene diterpenoids, ent-15α-angeloyloxykaur-16-en-3β-ol (7) and ent-15α-angeloyloxykaur-16-en-3β,9-diol (8), were extracted from the aerial parts of Distichoselinum tenuifolium, and six new derivatives were synthesised from compound (7). The antitumour properties of these natural and derivative ent-kaurenes (2, 7, 913) were evaluated in three cancer cell lines: HT29 (colon cancer), HepG2 (hepatocellular carcinoma), and B16-F10 (murine melanoma). Among them, the synthesised ent-kaurene (13) containing an exomethylene–cyclopentanone moiety showed the strongest antiproliferative effects in all cell lines tested, with significantly lower IC50 values around 2.5 μM. Compounds 13 and 12, together with their precursor (7), were selected for further comparative cytometric and microscopic analyses. Cell cycle studies revealed that derivatives 12 and 13 exhibited promising cytostatic activity by inducing selective G2/M phase arrest, particularly effective in HT29 and HepG2 cells. Conversely, precursor (7) showed no significant effect on B16-F10 cell cycle distribution. The Annexin V-FITC/PI double staining assay confirmed the robust apoptotic effects of compounds (7), 12 and 13, with compound 13 inducing up to 99% total apoptosis and exhibiting significant apoptotic activity in all cell lines tested. These apoptotic effects were closely linked to mitochondrial dysfunction, as evidenced by a marked loss of mitochondrial membrane potential and reduced Rh123 fluorescence in treated cells, thereby activating the intrinsic apoptotic pathway. These findings highlight the critical role of mitochondrial disruption in the cytotoxic mechanisms of these ent-kaurenes and underscore their potential as promising anticancer agents. Full article
(This article belongs to the Special Issue Small Molecule Drug Design and Research: 3rd Edition)
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23 pages, 7747 KiB  
Article
Supercomputer-Based Virtual Screening for Deoxyribonucleic Acid Methyltransferase 1 Inhibitors as Novel Anticancer Agents
by Lara Johanna Friedrich, Axel Guthart, Min Zhou, Paola B. Arimondo, Thomas Efferth and Mona Dawood
Int. J. Mol. Sci. 2024, 25(22), 11870; https://doi.org/10.3390/ijms252211870 - 5 Nov 2024
Viewed by 1361
Abstract
Targeting epigenetics is a new strategy to treat cancer and develop novel epigenetic drugs with anti-tumor activity. DNA methyltransferases transfer the methyl group from S-adenosyl-L-methionine (SAM) to the cytosine residue in a CpG island, leading to the transcription silencing of the gene. [...] Read more.
Targeting epigenetics is a new strategy to treat cancer and develop novel epigenetic drugs with anti-tumor activity. DNA methyltransferases transfer the methyl group from S-adenosyl-L-methionine (SAM) to the cytosine residue in a CpG island, leading to the transcription silencing of the gene. Hypermethylation can frequently be observed in several tumor types. Hence, the inhibition of DNMT1 has become a novel approach to cure cancer. In this study, virtual screening and molecular docking were performed for more than 11,000 ligands from the ZINC15 database to discover new hypomethylation agents. Four candidate compounds were further tested for their effects on DNMT1 in silico and in vitro. Compounds 2 and 4 showed the best DNMT1 inhibitory activity, but only compound 4 was able to inhibit the growth of several cancer cell lines. The hypomethylation of the luciferase gene by compound 4 was verified by a CMV- luciferase assay using KG-1 cells. Additionally, compound 4 suppressed cell migration in a dose- and time-dependent manner in the wound healing assay. Moreover, cell cycle analyses demonstrated that compound 4 arrested CCRF-CEM cells and MDA-MB-468 cells in the G0/G1 phase. Also, compound 4 significantly induced early and late apoptosis in a dose-dependent manner. In conclusion, we introduce compound 4 as a novel DNMT1 inhibitor with anticancer activity. Full article
(This article belongs to the Special Issue Small Molecule Drug Design and Research: 3rd Edition)
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