After attending both the “Decade to Educate in the Sustainable Development and the Agenda 30 of the UNESCO” and the “ACS GCI Pharmaceutical Roundtable”, which focused on sustainable chemistry, in this article, a green chemistry contribution to the Kamal Qureshi protocol is offered; thus, DIM^® and several of its analogs (3,3′-diindolylmethanes) were suitably produced under the green chemistry protocol. In the first stage, the substrate indol-3-yl carbinol was evaluated using mechanochemistry (the best mode) in comparison to other activating methods (near-infrared and microwave electromagnetic irradiation and ultrasound), wishing to highlight the employment of both TAFF^®, an excellent and well-characterized natural catalyst (bentonitic clay), and acetone, a green solvent, in addition to the analysis of the procedures in real-time. In the second stage, the mechanochemical methodology was extended to produce a set of fifteen DIMs, in the last stage, the use of a green metric exhibited the greenness of the approach, with it being important to highlight that, to our knowledge, after a search in the literature, this is the first time that the process has been evaluated to demonstrate its greenness.

Perezone, a sesquiterpene quinone, was the first natural product isolated in crystalline form on the American continent in 1852. It is commonly found in the roots of herbs from the Acourtia species (formerly Perezia). This molecule, along with its synthetic isomer isoperezone, exhibits antineoplastic effects, among others. In this study, an enzymatic reaction (green chemistry) was employed to oxidize the C12−C13 double bond of perezone and isoperezone. This method proved to be more effective than traditional toxic chemical oxidants. As result, epoxides were obtained, followed by acetonides, diols, and esters. All compounds were successfully synthesized and characterized using standard spectroscopic techniques. In breast cancer cell tests, the isoperezone acetonide showed the highest cytotoxicity, with an IC₅₀ of 8.44 µM. Additionally, a computational study was performed at the DFT (B3LYP) level of theory, indicating that the geometrical and energy differences between 6-R and 6-S stereoisomers are 0.5 kcal/mol, and the spectroscopic and electronic properties aligned with the experimental data. Finally, molecular docking revealed binding energies of −8.14 kcal/mol for 6-R and −8.04 kcal/mol for 6-S, with a hydrogen bond of 2.9 Å involving the His121 residue. A chemoinformatic prediction was also conducted to compare cytotoxicity results.

PARP-1 and COX-2 have played important roles in several carcinomas, representing potential therapeutic targets; natural products have constituted interesting alternatives in cancer research, and complementary computational methods are relevant tools for the proposal of new molecules. Therefore, in this work, a theoretical study of a set of four derivatives of perezone and isoperezone, i.e., α-pipitzol, β-pipitzol, α-isopipitzol, and β-isopipitzol, employing quantum chemistry, bioinformatics, and docking, was performed. Conformational studies were accomplished to obtain minimum energy structures. Subsequently, they were optimized by the B3LYP hybrid method and the 6-311++G(d,p) basis set. With this same level of theory, the geometrical, electronic, and spectroscopic properties and the reactivity parameters were determined; moreover, a molecular docking evaluation was performed to determine their activity towards COX-2 and PARP-1. Additionally, a cytotoxicity activity assay was performed against various cancer cell lines; thus, α-pipitzol and β-pipitzol showed the greatest affinity for COX-2, and the α-isopipitzol exhibited two relevant interactions. Regarding α-pipitzol, it exhibited both affinity and an important interaction with PARP-1. Regarding β-pipitzol, it displayed the lowest inhibitory concentration in A549 (64.49 µM); nevertheless, α-isopipitzol presented the lowest inhibitory concentrations, 83.59 µM and 87.85 µM for U37 and MCF-7 cell lines, respectively.

The design, production, and study of new poly[ADP-ribose] polymerase 1 (PARP-1) inhibitors have emerged as an interesting exploration area, since PARP-1 is an overexpressed enzyme in several carcinomas. In this sense, menadione, or vitamin K3, is well known for its use in correct blood clotting, and for the generation of reactive oxygen species, but it is important to mention that it has been used as an antineoplastic agent against several cell lines. Related to the last commentary, in this work, four novel molecules (2–5) were produced from menadione through a Michael addition protocol, using 1,2-ethanedithiol, cysteamine, benzene-1,4-dithiol, and 4-aminobenzenethiol as nucleophiles, and menadione (1) as substrate, to evaluate them as plausible candidates to inhibit PARP-1. It is convenient to note that after their production and spectroscopic characterization, both docking and theoretical studies for each compound were conducted, using density functional theory (DFT) with the hybrid method B3LYP with the 6-311G(d,p) basis set. As a complement, the reactivity properties determined by DFT calculations were obtained for all compounds; the results revealed that 2 has the best properties to bind with PARP-1, and 3 offered good results. Hence, the target compounds were evaluated in vitro, determining their activity against PARP-1, using olaparib as a reference. Molecules 2 and 3 displayed the free binding energy values −7.97 and −9.35 kcal/mol, respectively, but 2 has the best IC₅₀ value, 13.76 µM. It is important to highlight that 2 and 3 must be considered as potential new inhibitor agents against PARP-1, exhibiting competitive IC₅₀ values with olaparib.

A thorough review of pipitzols and isopipitzols, covering the period 1852–2026, is presented. Perezone, the precursor of these compounds, is considered to be the first secondary metabolite isolated on the American continent, a phyto-molecule widely studied with regard to its spectra, chemical transformations, and especially its isolation and pharmacological activities. Perezone has several isomers: isoperezone, a synthetic molecule; and α- and β-pipitzols, two natural isomers of cedrenoid type achieved by thermal exo [4+2] cycloadditions. Isoperezone can be isomerized to β-isopipitzol through an endo [4+2] cycloaddition, while α-isopipitzol can be obtained from perezone by a [1+3] dipole addition. For this review, we conducted a comprehensive literature search, employing the main Scopus, SciFinder^®, and ResearchGate databases, which identified 148 references. We found that the most recent report on α- and β-pipitzols appeared in 2024, on α-isopipitzol appeared on 2 September 2026, and on the four isomers was published on 29 January 2026.

The use of computational tools has become widespread in drug discovery as an effective approach to guide the development of new therapeutic agents, including potential cancer drugs. In addition, plant-derived secondary metabolites have attracted considerable interest as a valuable source of bioactive compounds. Among these, alkannin and shikonin, two enantiomeric phyto naphthoquinones, have emerged as promising candidates for cancer therapy because of their anti-inflammatory properties and their ability to induce oxidative DNA damage in malignant cells. Related to the above commentaries, in the present study, the phyto naphthoquinones alkannin, shikonin, and their corresponding indole derivatives were evaluated employing density functional theory (DFT), followed by chemoinformatic analyses and molecular docking studies to evaluate, in silico, their potential activity against the cancer-related enzymes PARP-1, COX-2, and HDAC2, which are overexpressed in several types of cancer. The presence of the indole moiety in the phytomolecules increased their chemical reactivity, as exhibited by the calculated properties and the smaller LUMO–HOMO energy gap. In addition, the bioinformatic evaluation predicted that the target molecules may act as potential apoptosis agonists and antineoplastic agents. Finally, the performed molecular docking analysis suggested a stereoselective effect on the stability of ligand–protein binding complexes, particularly for alkannin, including relevant interactions with His201 and its indole derivative displaying interactions with His201, Tyr235, and Glu327 from the PARP-1 catalytic triad. Additionally, alkannin (−11.2 kcal/mol) and the corresponding indole derivative of shikonin (−10.14 kcal/mol) showed better interaction energies with COX-2 than naproxen (−8.75 kcal/mol). In the latter case, the inclusion of the indole moiety improved the binding affinity. In contrast, the affinity of the target compounds for HDAC2 decreased considerably with the indole derivatives in comparison with the reference compound BIZ.