The influence of thioether-substituted ligands in dicopper(II) complexes: Enhancing oxidation and biological activities.

This paper describes the synthesis, structural analysis, as well as the magnetic and spectroscopic characterizations of three new dicopper(II) complexes with dinucleating phenol-based ligands containing different thioether donor substituents: aromatic (1), aliphatic (2) or thiophene (3). Temperature-dependent magnetometry reveals the presence of antiferromagnetic coupling for 1 and 3 (J = -2.27 cm-1 and -5.01 cm-1, respectively, H = -2JS1S2) and ferromagnetic coupling for 2 (J = 5.72 cm-1). Broken symmetry DFT calculations attribute this behavior to a major contribution from the dz2 orbitals for 1 and 3, and from the dx2-y2 orbitals for 2, along with the p orbitals of the oxygens. The bioinspired catalytic activities of these complexes related to catechol oxidase were studied using 3,5-di-tert-butylcatechol as substrate. The order of catalytic rates for the substrate oxidation follows the trend 1 > 2 > 3 with kcat of (90.79 ± 2.90) × 10-3 for 1, (64.21 ± 0.99) × 10-3 for 2 and (14.20 ± 0.32) × 10-3 s-1 for 3. The complexes also cleave DNA through an oxidative mechanism with minor-groove preference, as indicated by experimental and molecular docking assays. Antimicrobial potential of these highly active complexes has shown that 3 inhibits both Staphylococcus aureus bacterium and Epidermophyton floccosum fungus. Notably, the complexes were found to be nontoxic to normal cells but exhibited cytotoxicity against epidermoid carcinoma cells, surpassing the activity of the metallodrug cisplatin. This research shows the multifaceted properties of these complexes, making them promising candidates for various applications in catalysis, nucleic acids research, and antimicrobial activities.

Spectroscopical and Molecular Studies of Four Manganese(I) PhotoCORMs with Bioinspired Ligands Containing Non-Coordinated Phenol Groups.

Carbonyl compounds are widely explored in medicinal inorganic chemistry and have drawn attention due to their signaling functions in homeostasis. Carbon-monoxide-releasing molecules (CORMs) were developed with the purpose of keeping the CO inactive until its release in the intracellular environment, considering its biological relevance. However, for therapeutic applications, the mechanisms of photorelease and which electronic and structural variations influence its rates must be fully understood. In this work, four ligands containing a pyridine, a secondary amine, and a phenolic group with different substituents were used to prepare new Mn(I) carbonyl compounds. Structural and physicochemical characterization of these complexes was carried out and confirmed the proposed structures. X-ray diffractometry structures obtained for the four organometallic compounds revealed that the substituents in the phenolic ring promote only negligible distortions in their geometry. Furthermore, UV-Vis and IR kinetics showed the direct dependence of the electron-withdrawing or donating ability of the substituent group, indicating an influence of the phenol ring on the CO release mechanism. These differences in properties were also supported by theoretical studies at the DFT, TD-DFT, and bonding situation analyses (EDA-NOCV). Two methods were used to determine the CO release constants (kCO,old and kCO,new), where Mn-HbpaBr (1) had the greatest kCO by both methods (Kco,old = 2.36 × 10-3 s-1 and kCO,new = 2.37 × 10-3 s-1). Carbon monoxide release was also evaluated using the myoglobin assay, indicating the release of 1.248 to 1.827 carbon monoxides upon light irradiation.

Shedding light on the physical nature of ion pair interactions involving carba-closo-dodecaborate anions. Insights from computation.

closo-Carboranes are structures that have been studied for many decades due to their vast applicability in medicine, catalysis, and energy storage. In order to go deeper into the physics behind the interactions of oppositely charged ions, which have potential applications in electrical energy storage and conversion devices, the present work aims to shed light on the physical nature of the interactions involving (R-CB11H11-, R = H, F, CH3, CF3) and Mq+ = Li+, Na+, Mg2+, Zn2+ ions. The bonding situations are evaluated in light of both canonical Kohn-Sham energy decomposition, EDA-NOCV, and local energy decomposition, LED, analyses. Electron and hole transports are also evaluated through charge transfer integrals. The findings reveal that such complexes present not only more significant electrostatic, but also non-negligible orbital contributions. Both energy decomposition analyses EDA-NOCV and DLPNO-LED confirm that the strength of ionic pair interactions (R-CB11H11- ↔ Mq+) is much more dependent on the nature of the cation employed than on the substituent R used. The results also reveal that charge transfers are not significant in such interacting systems.

Investigating the Solvent Effects on Binding Affinity of PAHs-ExBox4+ Complexes: An Alchemical Approach.

Polycyclic aromatic hydrocarbons (PAHs) are polluting agents, produced naturally or artificially, widely dispersed in the environment and potentially carcinogenic and immunotoxic to humans and animals, mainly for marine life. Recently, a tetracationic box-shaped cyclophane (ExBox4+) was synthesized, fully characterized, and revealed to form host-guest complexes with PAHs in acetonitrile, demonstrating the potential ability for it to act as a PAHs scavenger. This work investigates, through Molecular Dynamics (MD) simulations, the binding affinity between different PAHs and ExBox4+ in different solvents: chloroform (nonpolar), acetonitrile (polar protic), and water (polar protic). An alchemical method of simultaneous decoupling-recoupling (SDR) was used and implemented in a newly developed Python program called GHOAT, which fully automates the calculation of binding free energies and invokes the AMBER 2020 simulation package. The results showed that the affinity between ExBox4+ and PAHs in water is much larger than in organic media, with free energies between -5 and -20 kcal/mol, being able to act as a PHAs scavenger with great potential for applications in environmental chemistry such as soil washing. The results also reveal a significant correlation with the experimental available ΔG values. The methodology employed presents itself as an important tool for the in silico determination of binding affinities, not only available for charged cyclophanes but also extensible to several other HG supramolecular systems in condensed media, aiding in the rational design of host-guest systems in a significant way.

Overreact, an in silico lab: Automative quantum chemical microkinetic simulations for complex chemical reactions.

Today's demand for precisely predicting chemical reactions from first principles requires research to go beyond Gibbs' free energy diagrams and consider other effects such as concentrations and quantum tunneling. The present work introduces overreact, a novel Python package for propagating chemical reactions over time using data from computational chemistry only. The overreact code infers all differential equations and parameters from a simple input that consists of a set of chemical equations and quantum chemistry package outputs for each chemical species. We evaluate some applications from the literature: gas-phase eclipsed-staggered isomerization of ethane, gas-phase umbrella inversion of ammonia, gas-phase degradation of methane by chlorine radical, and three solvation-phase reactions. Furthermore, we comment on a simple solvation-phase acid-base equilibrium. We show how it is possible to achieve reaction profiles and information matching experiments.

Nature of hydride and halide encapsulation in Ag8 cages: insights from the structure and interaction energy of [Ag8(X){S2P(OiPr)2}6]+ (X = H-, F-, Cl-, Br-, I-) from relativistic DFT calculations.

Unraveling the different contributing terms to an efficient anion encapsulation is a relevant issue for further understanding of the underlying factors governing the formation of endohedral species. Herein, we explore the favorable encapsulation of hydride and halide anions in the [Ag8(X){S2P(OPr)2}6]+ (X- = H, 1, F, 2, Cl, 3, Br, 4, and, I, 5) series on the basis of relativistic DFT-D level of theory. The resulting Ag8-X interaction is sizable, which decreases along the series: -232.2 (1) > -192.1 (2) > -165.5 (3) > -158.0 (4) > -144.2 kcal mol-1 (5), denoting a more favorable inclusion of hydride and fluoride anions within the silver cage. Such interaction is mainly stabilized by the high contribution from electrostatic type interactions (80.9 av%), with a lesser contribution from charge-transfer (17.4 av%) and London type interactions (1.7 av%). Moreover, the ionic character of the electrostatic contributions decreases from 90.7% for hydride to 68.6% for the iodide counterpart, in line with the decrease in hardness according to the Pearson's acid-base concept (HSAB) owing to the major role of higher electrostatic interaction terms related to the softer (Lewis) bases. Lastly, the [Ag8{S2P(OPr)2}6]2+ cluster is able to adapt its geometry in order to maximize the interaction towards respective monoatomic anion, exhibiting structural flexibility. Such insights shed light on the physical reasoning necessary for a better understanding of the different stabilizing and destabilizing contributions related to metal-based cavities towards favorable incorporation of different monoatomic anions.

Supersaturating drug delivery systems containing fixed-dose combination of two antihypertensive drugs: Formulation, in vitro evaluation and molecular metadynamics simulations.

The purpose of this study was to associate the poorly water-soluble antihypertensive drugs candesartan cilexetil (CC) and hydrochlorothiazide (HCTZ) as fixed-dose combination, in the form of ternary Amorphous Solid Dispersions (ASD), using hydroxypropylmethylcellulose acetate succinate (HPMCAS) type M as polymeric carrier. The potential of the system to generate and to maintain supersaturation of both drugs was also evaluated. The ASDs were prepared by ball milling technique and solid-state characterization was performed by differential scanning calorimetry (DSC), Fourier transformed infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). Interaction between drugs and polymer in solid-state was evaluated by molecular metadynamics simulations. In vitro supersaturation profiles were determined in biorelevant medium. Physicochemical stability of ASDs was also evaluated under different storage conditions. Amorphization of both drugs was confirmed by solid-state characterization techniques. Molecular metadynamics simulations indicated that CC has stronger interaction with HMPCAS than HCTZ. In vitro supersaturation studies have shown that ternary ASDs could generate and maintain supersaturation of both drugs in biorelevant medium. The polymer reduced the desupersaturation of both drugs. Ternary ASDs also showed physicochemical stability over a period of 90 days, demonstrating the potential of the polymer in reducing the drugs recrystallization over the time. Ternary ASDs of CC, HCTZ and HPMCAS can be considered a promising system to associate the drugs as fixed-dose combinations. Also, these systems generate and maintain supersaturation of both drugs in biorelevant medium, with great storage stability. HPMCAS M was a good carrier for reducing the desupersaturation of associated HCTZ and CC.

The usefulness of energy decomposition schemes to rationalize host-guest interactions.

This perspective focuses on the crucial role that energy decomposition schemes play in elucidating the physical nature of non-covalent interactions in supramolecular systems, particularly from the point of view of host-guest systems stabilized by non-covalent interactions, which are fundamental to molecular recognition. The findings reported here reveal the robustness and practical application of methods such as EDA-NOCV in rationalizing molecular recognition situations in systems such as calixarenes, cyclophanes and other box-shaped hosts, capable of incorporating different chemical species as anions and PAHs. We expect that the discussed cases in this perspective can be viewed as an initial assessment for the multidimensional nature of the weak interactions underlying supramolecular aggregations, which can be recognized in a plethora of different structures constantly synthesized and characterized by chemists around the world.

The bonding situation in heteromultimetallic carbonyl complexes.

The synthesis and characterization of heteromultimetallic complexes has been one of the biggest challenges faced by inorganic chemists in the last few years. Here, the physical nature behind the relative stability of tri-heteronuclear complexes, involving the [M(PR3)]+ (M = Au(i), Ag(i) and Cu(i); and R = Ph and H) cation bridged by the [Fe(CO)4]2- anion, at the relativistic DFT-D3 level of theory is presented. Although the synthetic route to afford the [Fe(CO)4(AuPPh3)2] complex has been known for a long time, information about its copper and silver counterparts is scarce. The bonding situation is addressed via Kohn-Sham molecular orbitals coupled with a canonical energy decomposition analysis as the primary technique. The results show that complexes whose metal portion M-Fe-M is bent are more stable than linear ones. This stems from the dispersive interactions between the phenyl groups, but this also supports the presence of aurophilic d10-d10 interactions. The bonding between the [Fe(CO)4]2- and [Au-PPh3]+ fragments has a chiefly electrostatic character, but orbital interactions also represent a non-negligible role, as evidenced by the presence of : (i) σ-donation from the iron-carbonyl groups to the metal-phosphorus fragment; (ii) small π-donation from the metal to the iron center; and (iii) inner fragment polarization. The description of the metal-metal bonding situation in these complexes provides valuable information, useful to guide the synthesis of unprecedented multimetallic complexes containing coinage metals and other transition metals.

What is the driving force behind molecular triangles and their guests? A quantum chemical perspective about host-guest interactions.

The physical nature of host-guest (HG) interactions occurring between molecular triangles and linear anions was explored using density functional theory (DFT) calculations combined with energy decomposition analyses (EDA), nuclear independent chemical shift (NICS), and non-covalent interaction index (NCI). We demonstrate that: (i) in addition to the host being significantly rigid, the strain energies are not negligible, especially for host 2; (ii) halogen anions interact mainly by electrostatic forces (ΔEelst > ΔE > ΔEdisp), meanwhile; (iii) trihalogen anions interact mostly by dispersion forces (ΔEdisp > ΔEelst≈ΔE). The NICS and NCI calculations corroborate the idea that HG interactions are considerably mediated through dispersion terms, and also indicate an antiaromatic character inside the host walls.

Are DFT Methods Able to Predict Reduction Potentials of Ruthenium Nitrosyl Complexes Accurately?

The nitric oxide (NO) molecule is directly related to important physiological and physiopathological processes. Ruthenium tetraammine nitrosyl complexes can release NO from the [RuIINO+]3+/[RuIINO0]2+ reduction potential. Experimentally, well established is the practice of determining the redox potential with relation to a reference redox pair. However, there is no agreement on the best methodology that allows the minimization of uncertainties, both experimental and theoretical results. Here, the reduction potential relative to a reference redox pair is obtained from calculated absolute potentials for the target complex: trans-[Ru(NO)(L)(NH3)4]3+/2+ and reference pair: [Ru(bpy)3]3+/2+. The correlation between the calculated and experimental reduction potentials strongly depend on the DFT functional chosen. The best results were obtained with the GGA functional BP86, which showed deviations lower than 200 mV. The assignment of explicit solvent, in addition to continuum solvent influence, also appears as a relevant factor.

In Silico Design of Cylindrophanes: The Role of Functional Groups in a Fluoride Selective Host.

Molecular recognition is the key driver in the formation of supramolecular complexes, enabling the selective encapsulation of specific guests. Here, we explore the delicate balance between different energetic terms in the formation of an efficient host for fluoride anions based on a cylindrophane structure, which can be achieved by the incorporation of ligand sites into a cyanuric acid based cyclophane framework, resulting a close proximity between the ammonium hydrogens and the anion. This study describes the character and contribution of different energetic and repulsive terms that favor the efficient inclusion of fluoride. Our findings are useful for further rational design and synthesis of efficient and highly selective fluoride hosts, which have been generally less well described than complexing agents for other halides.

Platinum-Triggered Bond-Cleavage of Pentynoyl Amide and N-Propargyl Handles for Drug-Activation.

The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions, the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.

Coordination among Bond Formation/Cleavage in a Bifunctional-Catalyzed Fast Amide Hydrolysis: Evidence for an Optimized Intramolecular N-Protonation Event.

A density functional theory (DFT) computational analysis, using the ωB97X-D functional, of a rapid amide cleavage in 2-carboxyphthalanilic acid (2CPA), where the amide group is flanked by two catalytic carboxyls, reveals key mechanistic information: (a) General base catalysis by a carboxylate coupled to general acid catalysis by a carboxyl is not operative. (b) Nucleophilic attack by a carboxylate on the amide carbonyl coupled to general acid catalysis at the amide oxygen can also be ruled out. (c) A mechanistic pathway that remains viable involves general acid proton delivery to the amide nitrogen by a carboxyl, while the other carboxylate engages in nucleophilic attack upon the amide carbonyl; a substantially unchanged amide carbonyl in the transition state; two concurrent bond-forming events; and a spatiotemporal-base rate acceleration. This mechanism is supported by molecular dynamic simulations which confirm a persistent key intramolecular hydrogen bonding. These theoretical conclusions, although not easily verified by experiment, are consistent with a bell-shaped pH/rate profile but are at odds with hydrolysis mechanisms in the classic literature.

ESI-QTof-MS characterization of hirsutinolide and glaucolide sesquiterpene lactones: Fragmentation mechanisms and differentiation based on Na+ /H+ adducts interactions in complex mixture.

Sesquiterpene lactones (SL) have been reported with various biological effects. Among the described SL skeletons, hirsutinolide and glaucolide have not been extensively studied by mass spectrometry (MS), especially how to distinguish them in organic matrices. Thus, this paper reports (1) a strategy of their differentiation based on MS behavior during the ionization and (2) a proposal of the fragmentation pattern for both SL-subtypes. ESI(+)-HRMS data of four isolated SL (hirsutinolides 1 and 3; glaucolides 2 and 4) were recorded by direct and UPLC water-sample combined injections. These analyses revealed that hirsutinolides and glaucolides formed [M+Na]+ ion during the operation of the direct MS injection, and ([M+Na]+ and [M+H-H2 O]+ ) and [M+H]+ ions were respectively observed for hirsutinolides and glaucolides during the operation of combined UPLC water and sample MS injection. Computational simulations showed that the complex hirsutinolide (1)-Na+ formed with a lower preparation energy compared with the complex glaucolide (2)-Na+ . However, despite their different behavior during the ionization process, ESI(+)-HRMS/MS analyses of 1-4 gave similar fragmentation patterns at m/z 277, 259, 241, and 231 that can be used as diagnostic ions for both skeletons. Moreover, the differentiation strategy based on the nature of the complex SL-adducts and their MS/MS fragmentation pattern were successfully applied for the chemical characterization of the extract from Vernonanthura tweedieana using UPLC-ESI-HRMS/MS. Among the characterized metabolites, SL with hirsutinolide and glaucolide skeletons showed the aforementioned diagnostic fragments and an ionization behavior that was similar to those observed during the water-sample combined injection.

Understanding the interplay between π-π and cation-π interactions in [janusene-Ag]+ host-guest systems: a computational approach.

Janusene is a symmetrical molecule that contains four benzene rings, with two of them forced to be in a vertical quasi-parallel face-to-face alignment. The unique physical nature of the transannular interactions and the electronic features of the region between the enforced parallel rings was tested with the complexation of Ag+ ion as a probe to evaluate the interplay between π-stacking and cation-π non-bonded interactions. The janusene framework and the [janusene-Ag]+ host-guest (H-G) system were analyzed through the introduction of substituent groups with different chemical natures and in different parts of the host framework. The janusenes were used to tune both π-stacking and cation-π interactions. Three modes of substitution (facial, lateral, and facial plus lateral) were explored to gain insight into the effects of such scaffold modifications on the dual non-bonded interactions. Our findings suggest that the η2:η2 silver coordination is the most stable interaction mode between the silver ion and the janusene parallel rings. The cation-π interaction in the host structure is stabilized by electron donating groups and destabilized by electron withdrawing groups. The stabilization effect is highlighted with substitutions on the facial and facial plus lateral modes, with the latter being due to additive cooperation between the substituent groups. The bonding analysis indicates that [janusene-Ag]+ complexes containing electron withdrawing groups in the facial and facial plus lateral substitution schemes are more stabilized by orbital interactions. Complexes with electron donating groups and the complexes with substituent groups in the lateral position are mainly stabilized by electrostatic interactions, although in all cases orbital and dispersive interactions are also essential to describe the bonding situation. We envisage that these results will guide the development of new systems with increased cation-π interaction capability.

Shedding light on the electronic structure of [Ru(η6-C16H16)(NH3)3]2+ complex: a computational insight.

Ruthenophanes have been recognized as potential candidates to the design of electrically conducting polymers, particularly due to their electrochemical, structural, and spectroscopic properties. The comprehension and rationalization of the metal-ligand interaction is fundamental to pave the way for future applications as the design of new conducting materials. For that reason, this investigation sheds light on the electronic details behind the cation-π interactions present in ruthenophanes by using [Ru(η6-C16H16)(NH3)3]2+ as a model. Zeroth-order symmetry-adapted perturbation theory (SAPT0) shows the interaction Ru(II)-[2.2]paracyclophane with a predominant covalent character. However, the hapticity analysis of [2.2]paracyclophane shows only two predominantly covalent Ru-C bonds, as highlighted by the total energy density, H(r), in the bond critical point (BCP) obtained from quantum theory of atoms in molecules (QTAIM) method, and by second-order stabilization energy, ΔE(2), related to the processes: π C-C → dσ or dπ Ru, achieved in the natural bond orbital (NBO) method. The other two Ru-C chemical bonds show a largely electrostatic character, as can be visualized from the delocalization index, DI, between the electron basins in the electron localization function (ELF) method. Remarkably, the interacting quantum atoms (IQA) method showed practically the same value of the total interaction energy, E[Formula: see text], between Ru and these C atoms and, then, corroborates the hapticity four of the ligand: [2.2]paracyclophane. Source function distribution presents a correlation with the electronic interactions between different groups in [Ru(η6-C16H16)(NH3)3]2+. Graphical Abstract The nature of the interactions between [Ru(NH3)3]2+ and [2.2]paracyclophane in [Ru(η6-C16H16)(NH3)3]2+ was investigated with different methods of energy decomposition and electron density analysis. This interaction has a predominantly covalent character. It was possible to observe that some Ru-C interactions have a larger covalent character, in contrast for other that are mainly ionic.

Evaluation of Lignans from Piper cubeba against Schistosoma mansoni Adult Worms: A Combined Experimental and Theoretical Study.

Six dibenzylbutyrolactonic lignans ((-)-hinokinin (1), (-)-cubebin (2), (-)-yatein (3), (-)-5-methoxyyatein (4), dihydrocubebin (5) and dihydroclusin (6)) were isolated from Piper cubeba seed extract and evaluated against Schistosoma mansoni. All lignans, except 5, were able to separate the adult worm pairs and reduce the egg numbers during 24 h of incubation. Lignans 1, 3 and 4 (containing a lactone ring) were the most efficient concerning antiparasitary activity. Comparing structures 3 and 4, the presence of the methoxy group at position 5 appears to be important for this activity. Considering 1 and 3, it is possible to see that the substitution pattern change (methylenedioxy or methoxy groups) in positions 3' and 4' alter the biological response, with 1 being the second most active compound. Computational calculations suggest that the activity of compound 4 can be correlated with the largest lipophilicity value.

Shedding Light on the Hydrolysis Mechanism of cis, trans-[Ru(dmso)4Cl2] Complexes and Their Interactions with DNA-A Computational Perspective.

Using several computational tools such as density functional theory analysis, docking, and MD simulations, we performed a study on cis, trans-[Ru(II)(dmso)4Cl2] complexes, which have therapeutic potential as antimetastatic agents, and their association with DNA. Kohn-Sham energy decomposition analysis reveals that dmso ligands have much smaller interaction energies compared to the chlorido ligands, and their substitution by aquo ligands induces an extra stabilization of the other metal-ligand bonds. Once the complex is hydrolyzed, the aquo ligands have the weakest interactions to the metallic center and therefore are more labile for substitution by a DNA atom. Molecular docking and molecular dynamics were employed to understand the complex preassociation to DNA, pointing to a higher affinity of the hydrolyzed complexes, as well as showing spontaneous binding events during the simulations. Our results are consistent with the experimentally available data that suggest a mechanism in which the complexes are quickly hydrolyzed in solution, before forming cross-links with the DNA molecule. We present a set of methods that could be used to optimize these complexes computationally, aiding in the development of new drugs based on transition metals.

In vitro cytotoxicity and structure-activity relationship approaches of ent-kaurenoic acid derivatives against human breast carcinoma cell line.

In this study, ent-kaurenoic acid derivatives were obtained by microbial transformation methodologies and tested against breast cancer cell lines (MCF-7). A multivariate quantitative-structure activity relationship (QSAR) analysis was performed taking into account both microbial transformation derivatives and other analogues previously reported in literature to give some insight into the main features behind the cytotoxic activity displayed by kaurane-type diterpenes against MCF-7 cells. The partial least square regression (PLS) method was employed in the training set and the best PLS model was built with a factor describing 69.92% of variance and three descriptors (logP, εHOMO and εHOMO-1) selected by the Ordered Predictors Selection (OPS) algorithm. The QSAR model provided reasonable regression (Q2 = 0.64, R2 = 0.72, SEC = 0.29 and SEV = 0.33). The model was validated by leave-N-out cross-validation, y-randomization and external validation (R2pred = 0.89 and SEP = 0.27). The selected descriptors indicated that the activity was mainly related to electronic parameters (HOMO and HOMO-1 molecular orbital energies), as well as to logP. These findings suggest that higher activity values are directly related with both higher logP and frontier orbital energy values. The positive relationship between these orbitals and the activity suggests that the ent-kaurenoic acid analogues interaction with the target involves charge displacement, which is entirely consistent with the literature. Based on these findings, three compounds were proposed and one of them was synthesized and tested. The experimental result confirmed the activity predicted by the model.