Linker Moiety Research Articles

Binuclear Complexes Supported by a Tetrapyridyl Ligand with a Bending Anthraquinodimethane Linker.

A tetrapyridyl ligand with a bending anthraquinodimethane linker has been synthesized, and its complexation with coinage metals has been examined. The treatment of the ligand with Ag(I) and Au(I) cations afforded binuclear complexes, wherein the two metal centers were in close proximity to the inside space of the ligand. X-ray analyses corroborated with theoretical calculations indicated that the ligand has reasonable flexibility toward a bending deformation of the linker moiety to provide a ligand pocket suitable for the proximal binuclear complexes, even though such deformations accompany a non-negligible amount of energetic cost. On the other hand, treatment with 2 equiv of Cu(I) salt afforded a binuclear complex, in which both copper atoms were coordinated at the periphery of the ligand.

In vitro cannabinoid receptor activity, metabolism, and detection in seized samples of CH-PIATA, a new indole-3-acetamide synthetic cannabinoid.

The rapidly evolving synthetic cannabinoid receptor agonist (SCRA) market poses significant challenges for forensic scientists. Since the enactment of a generic ban in China, a variety of new compounds have emerged capable of evading the legislation by carrying new structural features. One recent example of a SCRA with new linker and head moieties is CH-PIATA (CH-PIACA, CHX-PIATA, CHX-PIACA). CH-PIATA bears an additional methylene spacer in the linker moiety between the indole core and the traditional carbonyl component of the linker. This study describes detections in 2022 of this new SCRA in the United States, Belgium, and Scottish prisons. CH-PIATA was detected once in a seized powder by Belgian customs and 12 times in Scottish prisons in infused papers or resin. The metabolites of CH-PIATA were investigated via in vitro human liver microsome (HLM) incubations and eight metabolites were identified, dominated by oxidative biotransformations. A blood sample from the United States was confirmed to contain a mixture of SCRAs including CH-PIATA via presence of the parent and at least five of the metabolites identified from HLM incubations. Furthermore, this paper evaluates the intrinsic in vitro cannabinoid 1 and 2 (CB1 and CB2) receptor activation potential of CH-PIATA reference material and the powder seized by Belgian customs by means of β-arrestin 2 recruitment assays. Both the reference and the seized powder showed a weak activity at both CB receptors with signs of antagonism found. Based on these results, the expected harm potential of this newly emerging substance remains limited.

Platinum-Acridine Agents with High Activity in Cancers Expressing the Solute Carrier MATE1 (SLC47A1).

Platinum-acridine anticancer agents (PAs) containing acyclic (1 and 3) and heterocyclic (R)-3-aminopiperidine (2) and 2-iminopyrrolidine (4) based linker moieties were studied. Similar to 1, rigidified 2 shows a strong positive correlation between potency and SLC47A1 (multidrug and toxin extrusion protein 1, MATE1) gene expression levels across the NCI-60 panel of cancer cell lines. All derivatives show nanomolar activity in HepG2 (liver), NCI-H460 (lung), and MDA-MB-436 (breast), which express high levels of SLC47A1 (Cancer Cell Line Encyclopedia, CCLE). The PAs are up to 350-fold more potent than cisplatin. In a MATE1 inhibition assay, a significant reduction in activity is observed in the three cancer cell lines (4000-fold lower for HepG2). Molecular docking experiments provide insight into the compatibility of the structurally diverse set of PAs with MATE1-mediated transport. MATE1 is a predictive marker and actionable target that sensitizes cancer cells regardless of the tissue of origin to PAs.

Spherulitic Characterization and Hierarchical Structural Evaluation of Azacalixarene‐Polyethylene Glycol Copolymers Containing s‐Triazine Rings

AbstractThis study investigates the solid‐state structure of a copolymer composed of polyethylene glycol (PEG) and azacalixarene, which has two s‐triazine rings and two phenyl rings alternately crosslinked by amino groups. Azacalixarene derivatives containing a low‐molecular‐weight linker moiety and exhibiting an amorphous structure have been synthesized in previous studies; however, in this study, they are crystallized by the substitution of the linker moiety with PEG. The spherulites formed by the corresponding copolymer possess the ability to form higher‐order structures, growing up to a diameter of 1.7 mm depending on the crystallization conditions. The azacalixarene‐PEG copolymer forms negative spherulites via homogeneous nucleation and exhibits a lamellar period at 13.8 nm. The lamellar crystalline part itself is 5.8 nm in thickness; bulky amorphous regions are also observed in the copolymer structure. Reciprocal lattice analysis results reveal that the crystal parts form a packing structure similar to the crystal lattice of PEG. The promotion of spherulite growth is predicted to reflect the characteristics of the corresponding copolymer, which crystallizes while universally containing many amorphous regions.

Disulfide-incorporated lipid prodrugs of cidofovir: Synthesis, antiviral activity, and release mechanism

The double-stranded DNA (dsDNA) viruses represented by adenovirus and monkeypox virus, have attracted widespread attention due to their high infectivity. In 2022, the global outbreak of mpox (or monkeypox) has led to the declaration of a Public Health Emergency of International Concern. However, to date therapeutics approved for dsDNA virus infections remain limited and there are still no available treatments for some of these diseases. The development of new therapies for treating dsDNA infection is in urgent need. In this study, we designed and synthesized a series of novel disulfide-incorporated lipid conjugates of cidofovir (CDV) as potential candidates against dsDNA viruses including vaccinia virus (VACV) and adenovirus (AdV) 5. The structure-activity relationship analyses revealed that the optimum linker moiety was C2H4 and the optimum aliphatic chain length was 18 or 20 atoms. Among the synthesized conjugates, 1c exhibited more potency against VACV (IC50 = 0.0960 μM in Vero cells; IC50 = 0.0790 μM in A549 cells) and AdV5 (IC50 = 0.1572 μM in A549 cells) than brincidofovir (BCV). The transmission electron microscopy (TEM) images revealed that the conjugates could form micelles in phosphate buffer. The stability studies in the GSH environment demonstrated that the formation of micelles in phosphate buffer might protect the disulfide bond from glutathione (GSH) reduction. The dominant means of the synthetic conjugates to liberate the parent drug CDV was by enzymatic hydrolysis. Furthermore, the synthetic conjugates remained sufficiently stable in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and pooled human plasma, which indicated the possibility for oral administration. These results indicated 1c may be a broad-spectrum antiviral candidate against dsDNA viruses with potential oral administration. Moreover, modification of the aliphatic chain attached to the nucleoside phosphonate group was involved as an efficient prodrug strategy for the development of potent antiviral candidates.

Potential Induced Protonation of the Second Coordination Sphere in a Hangman-type Iron Porphyrin Complex Promotes HER: Insights via in Situ Raman Spectroelectrochemistry.

The iron-based porphyrin complex containing a bispyridine-based hanging unit termed Py2XPFe was previously used as an effective catalyst for the reduction of protons to molecular hydrogen in solution. Here, the molecular compound was immobilized on a modified gold electrode surface and investigated by spectroelectrochemical methods under catalytic conditions. Immobilization of the Py2XPFe was facilitated using a pyridine-based amine linker molecule grafted to the gold electrode by electrochemical amine oxidation. The linker molecule denoted in this report as Pyr-1 allows for effective coordination of the iron porphyrin compound to the modified gold surface through axial coordination of the pyridine component to the Fe center. Resonance Raman spectroelectrochemistry was performed on the immobilized catalyst in pH 7 buffer at increasing cathodic potentials. This facilitates the electrochemical hydrogen evolution reaction (HER) while concurrently allowing for the observation of the v4, v3, and v2 porphyrin marker bands, which are sensitive to oxidation and spin state changes at the metal center. The observed changes in these bands at decreasing potential indicate that the immobilized Py2XPFe exists in the formal high-spin FeIII state before being reduced to the low-spin FeII state resulting from axial interaction with the linker moiety. This FeII state likely acts as the precatalyst for the HER reaction. Surfaced enhanced Raman spectroelectrochemistry was also conducted on the system as the gold electrode provides a sufficient surface enhancement effect so as to observe the bonding nature of the pyridine substituents within the second coordination sphere. As the potential is lowered cathodically, the pyridine ring breathing modes at 999 cm-1 are shown to increase in intensity due to protonation, which reach an intensity saturated limit whereat HER is conducted. This suggests that in pH 7 buffer, the increase in cathodic potentials facilitates protonation of the pyridine-based second coordination sphere. The extent to which protonation occurs can be viewed as a function of decreasing potential due to an increase in proton flux at the immobilized catalyst which, at the required onset potential for catalysis, aids in the reduction of protons to molecular hydrogen.

Identification of a pH-Responsive Peptide-Paclitaxel Conjugate as a Novel Drug with Improved Therapeutic Potential.

A highly sensitive, nontoxic, hydrophilic cell-penetrating peptide (CPP = c[RGDKLAK]) was selected for the construction of an effective peptide-drug conjugate (PDC). A hydrophobic drug paclitaxel (PTX) was successfully conjugated with CPP via ester linkage with succinic acid (SA) as a pH-cleavable linker moiety. The characterization techniques employed in this study indicate the >95% purity of the resulting PDC (CPP-SA-PTX). The in vitro studies show that our proposed PDC exhibits enhanced stability (∼90%) and cytotoxicity (EC50 = 8.32 ± 0.09 nM). Besides the excellent solubility of PDC in water, the PTX effect on positive β-tubulin-III indicates that the drug releases retained pharmacological properties. Additionally, in vivo, therapeutic-dose treatment reveals the prominent tumor-growth inhibitory effects (2.82-3.24-fold) of PDC in tumor mice models. Subsequently, these observations confirmed that our novel-designed PDC (CPP-SA-PTX) adduct may serve as a promising therapeutic agent to treat glioblastoma.

Identification of post-mortem paliperidone metabolite in human blood by LC-Q-Orbitrap-MS.

Paliperidone is a widely used antipsychotic agent detected in many fatal intoxications and suicide cases. In forensic toxicology, the accurate determination of blood paliperidone concentrations is required to prove death by paliperidone poisoning. However, the lethal concentration of paliperidone in blood at autopsy differs from that at the time of death. In this study, we found that paliperidone was decomposed by hemoglobin (Hb) through the Fenton reaction in a temperature-dependent fashion. The mechanism underlying paliperidone decomposition involves the cleavage of its C-N bond linker moiety. The mass spectra obtained by liquid chromatography quadrupole orbitrap mass spectrometry (LC-Q-Orbitrap-MS) revealed the formation of 6-fluoro-3-(4-piperidinyl)benzisoxazole (PM1) in Hb/H2O2 solution incubated with paliperidone, as well as in the blood of individuals who died from intentional ingestion of paliperidone. These results suggest that PM1 is the only metabolite produced from paliperidone as a result of temperature-dependent, post-mortem changes induced by Hb via the Fenton reaction, and may be useful as a biomarker to correct for the concentration of paliperidone in blood at the time of death in clinical cases.

Ligand field tuning of d-orbital energies in metal-organic framework clusters

Linker functionalization is a common route used to affect the electronic and catalytic properties of metal-organic frameworks. By either pre- or post-synthetically installing linkages with differing linker moieties the band gap, workfunction, and exciton lifetimes have been shown to be affected. One overlooked aspect of linker functionalization, however, has been the impact on the metal d-orbital energies to which they are bound. The ligand field differences should result in substantial changes in d-splitting. In this study we use density functional theory (DFT) to study the energetics of d-orbital energy tuning as a function of linker chemistry. We offer a general descriptor, linker pKa, as a tool to predict resultant band energies in metal-organic frameworks (MOFs). Our calculations reveal that simple functionalizations can affect the band energies, of primarily metal d lineage, by up to 2 eV and illustrate the significance of this band modularity using four archetypal MOFs: UiO-66, MIL-125, ZIF-8, and MOF-5. Together, we show that linker functionalization dramatically affects d-energies in MOF clusters and highlight that linker functionalization is a useful route for fine-tuning band edges centered on the metals, rather than linkers themselves.

Total Synthesis of Campylobacter jejuni NCTC11168 Capsular Polysaccharide via the Intramolecular Anomeric Protection Strategy

The infection of Campylobacter jejuni results in a significant diarrhea disease, which is highly fatal to young children in unindustrialized countries. Developing a new therapy is required due to increasing antibiotic resistance. Herein, we described a total synthesis of a C. jejuni NCTC11168 capsular polysaccharide repeating unit containing a linker moiety via an intramolecular anomeric protection (iMAP) strategy. This one-step 1,6-protecting method structured the challenging furanosyl galactosamine configuration, facilitated further concise regioselective protection, and smoothed the heptose synthesis. The tetrasaccharide was constructed in a [2 + 1 + 1] manner. The synthesis of this complicated CPS tetrasaccharide was completed in merely 28 steps, including the preparation of all the building blocks, construction of the tetrasaccharide skeleton, and functional group transformations.

Abstract 570: Dual acting bone defender agents inhibit prostate cancer-mediated bone destruction

Abstract Introduction: Bone metastasis is clinically observed in approximately 90% of patients with advanced prostate cancer (PCa). Metastatic bone destruction is driven by a self-reinforcing process coupling osteoclast (OC)-mediated bone degradation to PCa growth, and where cell movement acts to keep these two cooperating cell types in close proximity and to move them across the bone surface. We sought to create a new class of therapeutics that would be highly effective at inhibiting PCa-mediated bone destruction by targeting both OC function and cell motility. Methods: We synthesized new chemical entities, termed Dual Acting Bone Defender agents (DABDs), that couple the small molecule anti-motility agent, KBU2046, with bisphosphonate (bis), through a chemical linker. Assays for in vitro efficacy included: cell migration and invasion, binding to bone mineral, inhibiting osteoclast (OC)-mediated bone destruction, inhibition of Raf1 phosphorylation and inhibition of protein prenylation. In vivo assays included intra-cardiac (IC) injection of human PCa cells into mice, followed by real time monitoring of tumor growth and bone destruction by IVIS and CT imaging, respectively. Findings: We successfully created a novel route of chemical synthesis allowing us to access and probe unique chemical space, providing for single small molecules with bis functional groups linked to a KBU2046 core through a linker moiety. DABDs retain the cellular and molecular characteristics of KBU2046 and bis. Like KBU2046, they inhibit PCa cell motility and phosphorylation of Raf1 on its activation motif. They also inhibit the motility of breast and lung cancer cells. Like bis, they inhibit OC-mediated bone mineral destruction, prenylation of Ras small GTPase proteins, and chemically bind hydroxyapatite. Administered prior to IC injection, DABDs are so effective that they prolong animal survival and inhibit bone destruction in a dose-dependent manner. In mice with established bone metastasis to the femur, after IC injection, DABDs inhibit the growth of tumors. Doses 3,000 fold higher than that required for efficacy had no clinical or critical organ toxicity. Conclusions: DABDs represent a new multifunctional class of therapeutic agents that inhibit PCa-mediated bone destruction and have a high potential for advancing clinical efficacy in PCa patients with bone metastasis. Citation Format: Fangfang Qiao, Ryan Gordon, Abhinandan Pattanayak, Katelyn O’Neill, Nina Chaika, Weining Chen, Rachel Rhatigan, Raymond Bergan. Dual acting bone defender agents inhibit prostate cancer-mediated bone destruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 570.

Rational Design and Lead Optimisation of Potent Antimalarial Quinazolinediones and Their Cytotoxicity against MCF-7.

Quinazolinedione is one of the most outstanding heterocycles in medicinal chemistry thanks to its wide ranges of biological activities including antimalarial, anticancer, and anti-inflammatory. TCMDC-125133 containing a quinazolinedione pharmacophore displays promising antimalarial activity and low toxicity, as described in the GlaxoSmithKline (GSK) report. Herein, the design and synthesis of novel quinazolinedione derivatives is described on the basis of our previous work on the synthesis of TCMDC-125133, where low-cost chemicals and greener alternatives were used when possible. The initial SAR study focused on the replacement of the valine linker moiety; according to the in silico prediction using SwissADME, concise four-step syntheses toward compounds 4-10 were developed. The in-house synthesized compounds 4-10 were assayed for antimalarial activity against P. falciparum 3D7, and the result revealed that only the compound 2 containing a valine linker was tolerated. Another round of lead optimization focused on the replacement of the m-anisidine moiety in compound 2. A library of 12 derivatives was prepared, and the antimalarial assay showed that potent antimalarial activity could be maintained by replacing the methoxy group in the meta position of the phenyl side chain with a fluorine or chlorine atom (21: IC50 = 36 ± 5 nM, 24: IC50 = 22 ± 5 nM). Further lead optimization is underway to enhance the antimalarial activity of this class of compound. The compounds included in the study possess little to no antiproliferative activity against MCF-7 cells.

Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers.

The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151. After systematically modifying the linker length and composition, we observed that subtle modification of just one atom of the linker moiety of ZZ151 resulted in remarkable changes in the formation of the ternary complex and thus dramatically affected the degradation activities. ZZ151 quickly, specifically, and effectively induced SOS1 degradation; displayed potent antiproliferation activities against a broad panel of KRAS mutant-driven cancer cells; and showed superior anticancer activities in the KRASG12D- and G12V-mutant xenografts in mice. ZZ151 is a promising lead for developing new chemotherapies targeting KRAS mutants.

Photosensitized Vicinal Sulfonylamination of Alkenes with Oxime Ester and DABCO·(SO2)2.

A metal-free photosensitized three-component reaction of oxime esters, alkenes, and DABCO·(SO2)2 was developed. This protocol could accommodate a wide substrate scope, including activated and unactivated alkenes and aryl and aliphatic carboxylic acid oxime esters, delivering a broad range of β-amino sulfones in moderate to high yields. The insertion of SO2 as a linker moiety allows the manipulation of the functionality in the reaction process, expanding the utility of oxime esters as bifunctional reagents.

Polyphenols with Anti-Inflammatory Properties: Synthesis and Biological Activity of Novel Curcumin Derivatives.

Herein, we describe the synthesis and evaluation of anti-inflammatory activities of new curcumin derivatives. The thirteen curcumin derivatives were synthesized by Steglich esterification on one or both of the phenolic rings of curcumin with the aim of providing improved anti-inflammatory activity. Monofunctionalized compounds showed better bioactivity than the difunctionalized derivatives in terms of inhibiting IL-6 production, and known compound 2 presented the highest activity. Additionally, this compound showed strong activity against PGE2. Structure-activity relationship studies were carried out for both IL-6 and PGE2, and it was found that the activity of this series of compounds increases when a free hydroxyl group or aromatic ligands are present on the curcumin ring and a linker moiety is absent. Compound 2 remained the highest activity in modulating IL-6 production and showed strong activity against PGE2 synthesis.

Linker size dependent mechanical properties of di-imine based molecular crystals

We have demonstrated the ability to modify the mechanical flexibility of molecular crystals by modulating the length of intervening linker moieties while keeping the terminal shape synthons the same.

Surface functionalization of ZnO nanoparticles by Schiff base oriented tetrapodal ligands at room temperature and their photocatalytic applications: A comparative account on effect of structure directing agent on photocatalysis

Surface modification of ZnO nanoparticles at room temperature and their photocatalytic activity • Synthesis of surface modified ZnO NPs i.e. P-ZnO, Q-ZnO, R-ZnO and S-ZnO by ligands P , Q , R and S respectively at room temperature of different shape and size. • Photocatalytic efficiency of P-ZnO, Q-ZnO, R-ZnO and S-ZnO towards photocatalytic degradation of Rh B dye in 90 min is ∼92%, 80%, 89% and 79% respectively. • ZnO nanoparticles modified by tetrapodal ligands having urea linker moieties (P-ZnO and R-ZnO) have shown very high photocatalytic degradation (∼89-92%). ZnO is very popular and extremely sought after semiconductor material and more so as in the nanocrystalline form. It is biocompatible having a tunable band gap (3-3.7 eV) at room temperature and popular for several optical properties of interest in many fields. Nanoparticles have a lot of surface defects which affect their stability, properties and applications. We use structure directing agents to control the morphology of ZnO nanoparticles and also to control surface defects. We utilised four Schiff base oriented tetrapodal ligands (P, Q, R and S) as the structure directing agents for synthesis of surface modified ZnO nanoparticles i.e. P-ZnO [nanospheres (50-55 nm)], Q-ZnO [nanorods of length (∼1-2 µm) and breadth (∼130-170 nm)], R-ZnO [fibrous/entangled mesh] and S-ZnO [nanorods of length (30-40 nm) and breadth (5-20 nm)] at room temperature i.e. 30-40°C. The application of P-ZnO, Q-ZnO, R-ZnO and S-ZnO are further explored for photocatalytic degradation of Rhodamine B dye under UV lamp (90 min). The efficiency of P-ZnO, Q-ZnO, R-ZnO and S-ZnO towards photocatalytic degradation of Rhodamine B dye was ∼92%, ∼80%, ∼89% and ∼79% respectively.

Metal capture and desorption abilities of two types of organized films of polyguanamine derivatives with cyclic moiety and bulky or flexible linkers

"Metal collection" by a monolayer of polyguanamine derivatives with a cyclic component and a flexible linker moiety can be realized at an air/water interface. Distinct differences between the properties of the two derivatives were confirmed for the desorption behavior of Pd2+ ions. The cyclic moiety that resulted from the formation of the organized films of the polyguanamine derivatives exhibited a cup-shaped conformation rather than a planar conformation. Since Cd2+ ions have the same valence as Pd, there was no significant difference between the interfacial monolayer of these derivatives in the collection behavior from the subphase. The origin of the observed difference is likely the tilt angle of the cyclic site due to the substitution of a linker unit. The combination of the distortion angle of the cyclic component and the ionic radius may produce a structure for which desorption of the collected metal cations is difficult.

Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout.

We report the first well-characterized selective chemical probe for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group ("aza-scan") into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one-atom replacement (C→N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ-748, with potency and selectivity demonstrated by cellular and biochemical target engagement, as well as thermal shift assays. Cocrystal structures of our aza-SAHA derivatives with HDAC10 provide a structural rationale for potency, and chemoproteomic profiling confirmed exquisite cellular HDAC10-selectivity of DKFZ-748 across the target landscape of HDAC drugs. Treatment of cells with DKFZ-748, followed by quantification of selected polyamines, validated for the first time the suspected cellular function of HDAC10 as a polyamine deacetylase. Finally, in a polyamine-limiting in vitro tumor model, DKFZ-748 showed dose-dependent growth inhibition of HeLa cells. We expect DKFZ-748 and related probes to enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines in both physiological and pathological settings.

Semisynthetic Derivatives of Pentacyclic Triterpenes Bearing Heterocyclic Moieties with Therapeutic Potential.

Medicinal plants have been used by humans since ancient times for the treatment of various diseases and currently represent the main source of a variety of phytocompounds, such as triterpenes. Pentacyclic triterpenes have been subjected to numerous studies that have revealed various biological activities, such as anticancer, antidiabetic, anti-inflammatory, antimicrobial, and hepatoprotective effects, which can be employed in therapy. However, due to their high lipophilicity, which is considered to exert a significant influence on their bioavailability, their current use is limited. A frequent approach employed to overcome this obstacle is the chemical derivatization of the core structure with different types of moieties including heterocycles, which are considered key elements in medicinal chemistry. The present review aims to summarize the literature published in the last 10 years regarding the derivatives of pentacyclic triterpenes bearing heterocyclic moieties and focuses on the biologically active derivatives as well as their structure–activity relationships. Predominantly, the targeted positions for the derivatization of the triterpene skeleton are C-3 (hydroxyl/oxo group), C-28 (hydroxyl/carboxyl group), and C-30 (allylic group) or the extension of the main scaffold by fusing various heterocycles with the A-ring of the phytocompound. In addition, numerous derivatives also contain linker moieties that connect the triterpenic scaffold with heterocycles; one such linker, the triazole moiety, stands out as a key pharmacophore for its biological effect. All these studies support the hypothesis that triterpenoid conjugates with heterocyclic moieties may represent promising candidates for future clinical trials.