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Pharmacological inactivation of antitumor drugs toward healthy cells is a critical factor in prodrug development. Typically, pharmaceutical chemists graft temporary moieties to existing antitumor drugs to reduce their pharmacological activity. Here, we report a platform able to generate the cytotoxic agent by intramolecular cyclization. Using phenanthridines as cytotoxic model compounds, we designed ring‐opened biaryl precursors that generated the phenanthridines through bioorthogonal irreversible imination. This reaction was triggered by reactive oxygen species, commonly overproduced in cancer cells, able to convert a vinyl boronate ester function into a ketone that subsequently reacted with a pendant aniline. An inactive precursor was shown to engender a cytotoxic phenanthridine against KB cancer cells. Moreover, the kinetic of cyclization of this prodrug was extremely rapid inside living cells of KB cancer spheroids so as to circumvent drug action. [ABSTRACT FROM AUTHOR]

Targeted cancer treatment is a promising, less invasive alternative to chemotherapy as it is precisely directed against tumor cells whilst leaving healthy tissue unaffected. The plant-derived enzyme horseradish peroxidase (HRP) can be used for enzyme prodrug cancer therapy with indole-3-acetic acid or the analgesic paracetamol (acetaminophen). Oxidation of paracetamol by HRP in the presence of hydrogen peroxide leads to N-acetyl-p-benzoquinone imine and polymer formation via a radical reaction mechanism. N-acetyl-p-benzoquinone imine binds to DNA and proteins, resulting in severe cytotoxicity. However, plant HRP is not suitable for this application since the foreign glycosylation pattern is recognized by the human immune system, causing rapid clearance from the body. Furthermore, plant-derived HRP is a mixture of isoenzymes with a heterogeneous composition. Here, we investigated the reaction of paracetamol with defined recombinant HRP variants produced in E. coli, as well as plant HRP, and found that they are equally effective in paracetamol oxidation at a concentration ≥ 400 µM. At low paracetamol concentrations, however, recombinant HRP seems to be more efficient in paracetamol oxidation. Yet upon treatment of HCT-116 colon carcinoma and FaDu squamous carcinoma cells with HRP–paracetamol no cytotoxic effect was observed, neither in the presence nor absence of hydrogen peroxide. [ABSTRACT FROM AUTHOR]

To study the DNA damage caused by a potent platinum–acridine anticancer agent (PA) in cancer cells, an assay based on biorthogonal post‐labeling using a click chemistry‐enabled, azide‐modified derivative (APA) was developed. The method involves biotinylation, affinity capture, and bead‐based enrichment of APA‐modified genomic DNA. The key steps of the assay were validated and optimized in model duplexes, including full‐length plasmids, restriction fragments, and a DNA ladder. Native DNA treated with APA and subsequently subjected to post‐labeling with a biotin affinity tag was enzymatically digested and fragments were analyzed by in‐line LC–MS and MS/MS. The monofunctional–intercalative adducts formed by APA in 5′‐pyrimidine/guanine sequences in double‐stranded DNA were quantitatively biotinylated by strain‐promoted 1,3‐dipolar cycloaddition chemistry. When applied to DNA extracted from A549 lung cancer cells, the assay in combination with qPCR amplification demonstrates that platinum–acridines form adducts in the gene sequences encoding pre‐ribosomal RNA, a potential pharmacological target of these agents. [ABSTRACT FROM AUTHOR]

In this contribution we report on the synthesis, characterization and application of water‐soluble zinc(II) phthalocyanines, which are decorated with four or eight umbelliferone moieties for photodynamic therapy (PDT). These compounds are linked peripherally to zinc(II) phthalocyanine by a triethylene glycol linker attached to pyridines, leading to cationic pyridinium units, able to increase the water solubility of the system. Beside their photophysical properties they were analyzed concerning their cellular distribution in human hepatocyte carcinoma (HepG2) cells as well as their phototoxicity towards HepG2 cells, Gram‐positive (S. aureus strain 3150/12 and B. subtilis strain DB104) and Gram‐negative bacteria (E. coli strain UTI89 and E. coli strain Nissle 1917). At low light doses and concentrations, they exhibit superb antimicrobial activity against Gram‐positive bacteria as well as anti‐tumor activity against HepG2. They are even capable to inactivate Gram‐negative bacteria, whereas the dark toxicity remains low. These unique water‐soluble compounds can be regarded as all‐in‐one type photosensitizers with broad applications ranges in the future. [ABSTRACT FROM AUTHOR]

Mechanically interlocked molecules (MIMs) carry great potential in different fields of chemistry, based on their specific structures, their internal dynamics, their stimuli‐responsive behavior, and other unique features of the mechanical bond. This minireview presents some of the most recent developments in their use for medical and biological applications. For example, they have been used to influence, enhance or block the action of therapeutic agents to enable targeted drug delivery. The dynamic structural properties have been used to generate switches and transporters, as well as sensors for various medically relevant species. Building MIMs by incorporating biomolecules like DNA and proteins has served as a novel way to control their properties. [ABSTRACT FROM AUTHOR]

We previously found that p97 ATPase inhibitors 2-(2-amino-1H-benzo[d]imidazol-1-yl)-N-benzyl-8-methoxyquinazolin-4-amine (ML240) and 2-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine (ML241) specifically target the D2 domain of wild-type p97. In addition, one of the major p97 cofactors, p47, decreases their potencies by ∼50-fold. In contrast, N(2) ,N(4) -dibenzylquinazoline-2,4-diamine (DBeQ) targets both the D1 and D2 domains and shows only a four- to sixfold decrease in potency against the p97-p47 complex. To elucidate structure-activity relationships for the inhibitors, we screened 200 p97 inhibitor analogues for their ability to inhibit the ATPase activity of either or both of the D1 or D2 domains, as well for their effects on p47 potency. The selectivity of 29 of these compounds was further examined by eight-dose titrations. Four compounds showed modest selectivity for inhibiting the ATPase activity of D1. Eleven compounds inhibited D2 with greater potencies, and four showed similar potencies against D1 and D2. p47 decreased the potencies of the majority of the compounds and increased the potencies of five compounds. These results highlight the possibility of developing domain-selective and complex-specific p97 inhibitors in order to further elucidate the physiological roles of p97 and its cofactors.

Aminopeptidase N (APN) was closely associated with cancer invasion, metastasis, and angiogenesis. Therefore, APN inhibitors have attracted more and more attention of scientists as antitumor agents. In the current study, we designed, synthesized, and evaluated one new series of pyrazoline-based hydroxamate derivatives as APN inhibitors. Moreover, the structure–activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound 14o with R1 = CH3, showed the best capacity for inhibiting APN with an IC50 value of 0.0062 ± 0.0004 μM, which was three orders of magnitude better than that of the positive control bestatin. Compound 14o possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 μM, compound 14o exhibited much better capacity for inhibiting the micro-vessel growth relative to bestatin in the rat thoracic aorta ring model. Additionally, the putative interactions of 14o with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His297, Glu298 and His301. Meanwhile, the terminal phenyl group and another phenyl group of 14o interacted with S2′ and S1 pockets via hydrophobic effects, respectively.

A series of new thiazolo[3,2-a]pyrimidines different by aryl substituents in 2 and 5 positions are synthesized and characterized in solution as well as in the crystalline phase using 1H and 13C NMR-, IR-spectroscopies, mass-spectrometry methods, and single crystal X-ray diffraction (SCXRD). The SCXRD study revealed the role of intermolecular H-bonding in the formation of supramolecular architectures (racemic monomers, centrosymmetric racematic dimers, or homochiral 1D chains) of obtained thiazolo[3,2-a]pyrimidines derivatives depending on solvents (aprotic DMSO or protic EtOH) used upon the crystallization process. Moreover, the in vitro study of cytotoxicity toward different tumor cells showed their high or moderate efficiency with moderate cytotoxicity against normal liver cells which allows to consider the obtained thiazolo[3,2-a]pyrimidine derivatives as promising candidates for application as antitumor agents.

Stimulating photosensitizers (PS) by Cerenkov radiation (CR) can overcome the light penetration limitation in traditional photodynamic therapy. However, separate injection of radiopharmaceuticals and PS cannot guarantee their efficient interaction in tumor areas, while co‐delivery of radionuclides and PS face the problem of nonnegligible phototoxicity in normal tissues. Here, we describe a 131I‐labeled smart photosensitizer, composed of pyropheophorbide‐a (photosensitizer), a diisopropylamino group (pH‐sensitive group), an 131I‐labeled tyrosine group (CR donor), and polyethylene glycol, which can self‐assemble into nanoparticles (131I‐sPS NPs). The 131I‐sPS NPs showed low phototoxicity in normal tissues due to aggregation‐caused quenching effect, but could self‐produce reactive oxygen species in tumor sites upon disassembly. Upon intravenous injection, 131I‐sPS NPs showed great tumor inhibition capability in subcutaneous 4T1‐tumor‐bearing Balb/c mice and orthotopic VX2 liver tumor bearing rabbits. We believed 131I‐sPS NPs could expand the application of CR and provide an effective strategy for deep tumor theranostics. [ABSTRACT FROM AUTHOR]

The β‐diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ2‐O,O'‐chelating ligands were used to construct Ru(II) complexes with polypyridyl co‐ligands, and their biological activity was evaluated. The complexes demonstrated promising structure‐dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ∼30‐fold window between cytotoxicity in a 3‐D tumor spheroid model and potential in vivo toxicity. These results suggest that κ2‐O,O'‐ligands can be incorporated into Ru(II)‐polypyridyl complexes to create favorable candidates for future drug development. [ABSTRACT FROM AUTHOR]

Near‐infrared (NIR)‐light‐triggered photothermal therapy (PTT) is usually associated with undesirable damage to healthy organs nearby due to the high temperatures (>50 °C) available for tumor ablation. Low‐temperature PTT would therefore have tremendous value for clinical application. Here, we construct a hypoxia‐responsive gold nanorods (AuNRs)‐based nanocomposite of CRISPR‐Cas9 for mild‐photothermal therapy via tumor‐targeted gene editing. AuNRs are modified with azobenzene‐4,4′‐dicarboxylic acid (p‐AZO) to achieve on‐demand release of CRISPR‐Cas9 using hypoxia‐responsive azo bonds. In the hypoxic tumor microenvironment, the azo groups of the hypoxia‐activated CRISPR‐Cas9 nanosystem based on gold nanorods (APACPs) are selectively reduced by the overexpression of reductases, leading to the release of Cas9 and subsequent gene editing. Owing to the knockout of HSP90α for reducing the thermal resistance of cancer cells, highly effective tumor ablation both in vitro and in vivo was achieved with APACPs under mild PTT. [ABSTRACT FROM AUTHOR]

Among poly(ADP‐ribose) polymerases (PARPs), PARP‐1 has emerged as a target in cancer therapy. The present work was aimed to design and synthesize O‐alkylaryl amidoximes as a new antiproliferative agents. The target compounds were designed through the study of molecular docking against the PARP‐1 and synthesized from commercially available starting materials in good yields under mild conditions and easy to perform reactions. The synthesized compounds exhibited in vitro antineoplastic activity (0.32–27.8 mM) against MCF‐7 and Caco‐2 cells, and one of them exhibited selective toxicity when tested against VERO cells. These compounds can be considered good candidates for the next stages in the development of new antiproliferative drugs. [ABSTRACT FROM AUTHOR]

The article presents the synthesis and study of the antimicrobial and antitumor activity of fusidic acid derivatives containing oxime, amino substituents, and a caprolactam ring. The introduction of a caprolactam fragment into the molecule provides a high antibacterial effect comparable to that of fusidic acid and contributes to a 5.8‐fold decrease in hemolytic activity compared to that of the native antibiotic. The presence of two oxime groups in the methylfusidate molecule ensures a high antiproliferative effect against H522 cells of non‐small cell lung cancer, leading to 57 % of the lethality of this cell line. [ABSTRACT FROM AUTHOR]

In this study, we document the first total synthesis of the marine cyanobacteria secondary metabolite 27-deoxylyngbyabellin A in 10 linear steps with 9.7% overall yield. Key steps entailed (1) one-pot cascade reaction of (S)-2-(benzyloxy)-3-methylbutanoic acid and of Boc- l -Ile-OH with a β-azido disulfide building block to access two critical thiazole units, (2) chiral oxazaborolidinone-mediated asymmetric aldol reaction to construct an (S)-β-hydroxy ester, and (3) diphenyl phosphorazidate mediated macrolactamization of the assembled linear precursor to achieve the natural product 27-deoxylyngbyabellin A. [ABSTRACT FROM AUTHOR]

Kinase inhibitors (KIs) represent a popular class of therapeutic agents and chemical probes but most of them tend to be polypharmacological. Receptor and non‐receptor Tyrosine KIs can target more than 100 kinases simultaneously compare to other KIs. We here analyze the molecular targets of 41 U.S. Food and Drug Administration (FDA)‐approved KIs. We chose 18 drugs (Tyrosine KIs) and sought out to evaluate their selectivity profile and engagement with a number of targets in vivo at clinically relevant doses. We also wanted to see whether there prevails any correlation between the target engagement profile and the reported side effects for specific KIs chosen as test cases. To explore all clinical targets of the 18 KIs, we considered the free (unbound) maximum serum concentration (Cmax) of each KI and only chose targets for which the cognate affinities lie within the reported free Cmax values, thereby allowing plausible interaction in clinical doses. We retrieved the side effects of those KIs that is reported in the FDA adverse event reporting system. We illustrate how correlation analysis of target‐side effect can give a new insight into the off target of KIs and their effect on increasing the toxicity of KIs. These analyses could aid our understanding of the structural‐activity relationship of KIs. [ABSTRACT FROM AUTHOR]

The first total synthesis of the actin‐stabilizing marine natural product geodiamolide H was achieved. Solid‐phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the stage for investigating the key ring‐closing metathesis. Geodiamolide H and synthetic analogues were characterized for their toxicity and for antiproliferative effects in cellulo, by characterising actin polymerization induction in vitro, and by docking on the F‐actin target and property computation in silico, for a better understanding of structure‐activity relationships (SAR). A non‐natural analogue of geodiamolide H was discovered to be most potent in the series, suggesting significant potential for tool compound design. [ABSTRACT FROM AUTHOR]

Stimulating photosensitizers (PS) by Cerenkov radiation (CR) can overcome the light penetration limitation in traditional photodynamic therapy. However, separate injection of radiopharmaceuticals and PS cannot guarantee their efficient interaction in tumor areas, while co‐delivery of radionuclides and PS face the problem of nonnegligible phototoxicity in normal tissues. Here, we describe a 131I‐labeled smart photosensitizer, composed of pyropheophorbide‐a (photosensitizer), a diisopropylamino group (pH‐sensitive group), an 131I‐labeled tyrosine group (CR donor), and polyethylene glycol, which can self‐assemble into nanoparticles (131I‐sPS NPs). The 131I‐sPS NPs showed low phototoxicity in normal tissues due to aggregation‐caused quenching effect, but could self‐produce reactive oxygen species in tumor sites upon disassembly. Upon intravenous injection, 131I‐sPS NPs showed great tumor inhibition capability in subcutaneous 4T1‐tumor‐bearing Balb/c mice and orthotopic VX2 liver tumor bearing rabbits. We believed 131I‐sPS NPs could expand the application of CR and provide an effective strategy for deep tumor theranostics. [ABSTRACT FROM AUTHOR]

Novel anticancer compounds and their precision delivery systems are actively developed to create potent and well‐tolerated anticancer therapeutics. Here, we report the synthesis of a novel anthracycline, Utorubicin (UTO), and its preclinical development as an anticancer payload for nanocarriers. Free UTO was significantly more toxic to cultured tumor cell lines than the clinically used anthracycline, doxorubicin. Nanoformulated UTO, encapsulated in polymeric nanovesicles (polymersomes, PS), reduced the viability of cultured malignant cells and this effect was potentiated by functionalization with a tumor‐penetrating peptide (TPP). Systemic peptide‐guided PS showed preferential accumulation in triple‐negative breast tumor xenografts implanted in mice. At the same systemic UTO dose, the highest UTO accumulation in tumor tissue was seen for the TPP‐targeted PS, followed by nontargeted PS, and free doxorubicin. Our study suggests potential applications for UTO in the treatment of malignant diseases and encourages further preclinical and clinical studies on UTO as a nanocarrier payload for precision cancer therapy. [ABSTRACT FROM AUTHOR]

Metal–organic frameworks (MOFs) hold great promise for biomedical applications owing to their unique properties. The porous structures make MOFs excellent candidates for the delivery of different drugs; the flexibility in choosing metal ions and organic ligands makes it feasible to prepare MOFs with intrinsic antitumor activities and further devise MOF–drug synergistic systems; many other types of antitumor agents could also be developed using MOFs as the precursors/templates. Thus, the past two decades have witnessed the great development of MOF‐based drugs, especially in the antitumor field. This Minireview mainly focuses on the design and applications of MOF‐based antitumor agents. Four aspects covering the whole field are introduced: MOFs as carriers, MOFs as antitumor agents, MOF–drug synergistic systems, and MOF‐derived antitumor agents. The challenges and opportunities of MOFs for clinical antitumor applications are also discussed. [ABSTRACT FROM AUTHOR]

The novel porphyrin‐based 5‐fluorouracil and its metal complexes were synthesized. Through the combination of porphyrin and anticancer drug 5‐fluorouracil (5‐FU), it provides ideas for how to maximize the antitumor activity of drugs. The new porphyrin and its metal complexes take advantage of the enrichment of porphyrins in tumor cells, which makes them have higher cytotoxicity to tumor cells than normal cells, thus reducing the toxic and side effects. Excellent photophysical properties were illustrated by UV‐vis absorption and emission spectra with enhanced absorbance between 650 and 750 nm and fluorescence emission within 600–800 nm. Besides, manganese porphyrin and non‐central metalloporphyrin were evaluated in vitro by 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide (MTT) assay against MCF‐7, HepG2, and HeLa. In addition, compared with free 5‐fluorouracil, the novel manganese porphyrin shows higher antitumor activity. Therefore, the novel manganese porphyrin‐based 5‐fluorouracil is a promising drug for cancer treatment due to its effective antitumor activity, and near‐infrared absorption. [ABSTRACT FROM AUTHOR]

A series of novel 4,5‐diphenyloxazol‐1,2,4‐triazole derivatives (6 a–6 l) were synthesized and screened for anticancer activity against the prostate lung cancer cell lines viz., PC‐93 and HBT‐55. The outcome of the investigation reveals that compounds 6 a, 6 b and 6 j showed potential anticancer activity against PC‐93 cell line with the half maximal inhibitory concentration (IC50) values of 13.12, 15.34, and 16.34 μM, respectively. Compounds 6 a, 6 d and 6 j exhibited potential anticancer activity against HBT‐55 cell line with IC50 value 17.28, 16.48, and 15.12 μM respectively, when compared to standard drug doxorubicin. Further, docking studies are performed to understand the possible interactions responsible for their potential activity by considering the Fibroblast growth factor receptor 1 (FGFR1) and the Ser‐/Thr‐specific kinase Akt protein (Akt) as target proteins. The amino acid residues from ALA639 to PRO741 of FGFR1 and from GLU17 to ASP292 of Akt proteins are involved in non‐covalent interactions with the ligands 6 a–6 l. The insilico pharmacokinetic properties are predicted for the molecules 6 a–6 l to assess the druggability. The study provides that compounds 6 a, 6 b, 6 d, and 6 j scaffolds serve as promising lead molecules for treating cancer and further structure optimizations. [ABSTRACT FROM AUTHOR]

G‐quadruplexes (G4s) are prevalent in oncogenes and are potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) complex (Pt1), whose affinity to G4‐DNA is activated by adaptive binding and selectivity controlled by binding kinetics. The resolved structure of Pt1/VEGF‐G4 (a promoter G4) shows that Pt1 matches 3′‐G‐tetrad of VEGF‐G4 through Cl−‐dissociation and loop rearrangement of VEGF‐G4. Binding rate constants are determined by coordination bond breakage/formation, correlating fully with affinities. The selective rate‐determining binding step, Cl−‐dissociation upon G4‐binding, is 2–3 orders of magnitude higher than dsDNA. Pt1 potently targets G4 in living cells, effectively represses VEGF expression, and inhibits vascular growth in zebrafish. We show adaptive G4‐binding activation and controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules. [ABSTRACT FROM AUTHOR]

Metal complexes play an essential role in pharmaceutical sciences for their multiple and important activities. Schiff bases are versatile pharmacophores able to form chelating complexes with several metals in different oxidation states. Complexes with Schiff bases are widely described in the literature for their multiple actions and numerous advantages, such as low cost and easy synthesis. They show multiple biological activities, including antimicrobial, antioxidant, antimalarial, antinflammatory and antitumor. Schiff bases may also form complexes with lanthanides and actinides acting as catalysts (e.g., in various synthetic processes) and antitumor agents. This review intends to extend on our previous paper regarding Schiff bases as antitumorals, highlighting the importance, in the field of the anticancer agents, of these tools as ligands of metal complexes. [ABSTRACT FROM AUTHOR]

The antitumor activity of Ti(IV)-based compounds put them in the spotlight for cancer treatment in the past, but their lack of stability in vivo due to a high rate of hydrolysis has hindered their development as antitumor drugs. As a possible solution for this problem, we have reported a synthesis strategy through which we combined a titanocene fragment, a tridentate ligand, and a long aliphatic chain. This strategy allowed us to generate a titanium compound (Myr-Ti) capable of interacting with albumin, highly stable in water and with cytotoxic activity in tumor cells[1]. Following a similar strategy, now we report the synthesis of a new compound (Myr-TiY) derived from titanocene Y that shows antitumoral activity in a cisplatin resistant model with a 50% inhibitory concentration (IC50) of 41–76 μM. This new compound shows high stability and a strong interaction with human serum albumin. Myr-TiY has a significant antiproliferative and proapoptotic effect on the tested cancer cells and shows potential tumor selectivity when assayed in non-tumor human epithelial cells being more selective (1.3–3.8 times) for tumor cells than cisplatin. These results lead us to think that the described synthesis strategy could be useful to generate compounds for the treatment of both cisplatin-sensitive and cisplatin-resistant cancers. New titanium complex containing a titanocene Y fragment, a tridentate ligand, and a long aliphatic chain that facilitates a non-covalent interaction with albumin. This compound shows tumor cell specificity and improved antitumor activity against platinum resistant human cancer cell lines. [Display omitted] • A novel Ti(IV) drug with cytotoxic activity against cisplatin resistant tumor cells. • Titanocene Y derivative interacts non-covalently with human serum albumin. • Albumin interaction may take place through a long aliphatic chain. [ABSTRACT FROM AUTHOR]

Herein we demonstrate a new strategy by introducing Se atom with strong polarization effects to obtain highly bioactive organoselenium with electrophilic center. Organoselenium interact with Cys16 and Thr18 of PDGFB in malignant osteosarcoma MG63 cells through non-covalent bond, which further block the activation of intracellular AKT/JNK and downstream signaling pathways to promote cancer cells apoptosis. [Display omitted] • Organic selenium with high bioactivity electrophilic center was synthesized. • Org-Se can target PDGFB protein in MG63 cells and promote apoptosis. • Org-Se combined with radiotherapy can promote apoptosis of MG63 cells. Growth factor-like proteins play an important role in promoting oncogenesis. Therefore, designing specific inhibitors of such targets would facilitate the development of targeted drugs with low toxicity. However, low affinity and poor specificity between drugs and target proteins always affect the selectivity and action efficacy. Herein we demonstrates a new strategy by introducing selenium (Se) atom with strong polarization effects to obtain highly bioactive organoselenium with electrophilic center. The results of target-capturing analysis reveals that organoselenium interact with Cys16 and Thr18 of the platelet-derived growth factor B (PDGFB) protein in malignant osteosarcoma MG63 cells through non-covalent bond, thus inhibiting the expression and activity of PDGFB, which further block the activation of intracellular protein kinase B/c-Jun N-terminal kinases (AKT/JNK) and downstream signaling pathways to promote cancer cells apoptosis. Taken together, we have developed a novel strategy by introducing Se-based electrophilic centers for the development of targeted therapeutic agents for malignant tumors. [ABSTRACT FROM AUTHOR]

Covalent organic frameworks (COFs) have generated interest as promising tools for reactive oxygen species (ROS) -mediated therapy owing to designable structures and diversified modification sites. However, the ordered porous structure of COFs and their multiple catalytic sites on the enhancement of ROS-mediated therapy of cancers have attached little attention. Here, we synthesized a nanosonosensitizer named FeTPD@GOx, consisting of the ferriporphyrin-based COF (Fe-COF) loaded with glucose oxidase (GOx) for pore-enhanced ROS-mediated therapy in which GOx catalyzed glucose to H 2 O 2 while Fe3+/Fe2+ cycle catalyzed H 2 O 2 to O 2 and ·OH. The H 2 O 2 /O 2 self-supply cycle inside the pores of COFs enhanced the generation of abundant ROS in situ upon ultrasound (US) irradiation. The mechanism examination revealed that the opening pore channels of COFs not only could catch O 2 with the rapid exchange for O 2 and 1O 2 , but also provided more accessible Fenton reaction sites to iron ions for more ·OH generation, enhancing the efficacy of sonodynamic therapy (SDT) and chemodynamic therapy (CDT). In vivo antitumor evaluation revealed that FeTPD@GOx can not only inhibit the growth of the proximal tumor effectively but also display superior antitumor efficiency to the distant tumor upon US irradiation. Our work, which utilizes the porous structure, multiple catalytic sites, and GOx loading of COFs to hold O 2 , thereby promoting gas exchange, realizing sequential catalytic reactions, amplifying ROS generation, and enhancing synergistic effect of SDT and CDT for ROS-mediated therapeutic efficacy, offers prospects for applications of COFs in biomedical fields. [Display omitted] • A nanosonosensitizer named FeTPD@GOx is synthesized for relative oxygen species (ROS)- mediated therapy. • The porous structure of COF can enhance 1O 2 and ·OH for sonodynamic therapy (SDT) and chemodynamic therapy (CDT). • In vivo antitumor evaluation showed that FeTPD@GOx can inhibit the growth of the both two side tumors upon US irradiation. [ABSTRACT FROM AUTHOR]

The family of polyhalogenated monoterpenes from Plocamium counts over a hundred known members. Using glyceraldehyde acetonide as a chiral-pool precursor, an enantioselective and divergent strategy was developed that provides a blueprint for the synthesis of many of the small yet complex acyclic members of this family. The broad applicability of this approach is demonstrated with the short, eight-step synthesis of four natural products and three analogues. These syntheses are the first of any members of the acyclic polyhalogenated Plocamium monoterpenes and permitted the evaluation of their selectivity against a range of tumor cell lines.

Abstract Drug resistance represents the major reason of pharmacological treatment failure. It is supported by a broad spectrum of mechanisms, whose molecular bases have been frequently correlated to aberrant protein phosphorylation. CK2 is a constitutively active protein kinase which phosphorylates hundreds of substrates; it is expressed in all cells, but its level is commonly found higher in cancer cells, where it plays anti-apoptotic, pro-migration and pro-proliferation functions. Several evidences support a role for CK2 in processes directly responsible of drug resistance, such as drug efflux and DNA repair; moreover, CK2 intervenes in signaling pathways which are crucial to evade drug response (as PI3K/AKT/PTEN, NF-κB, β-catenin, hedgehog signaling, p53), and controls the activity of chaperone machineries fundamental in resistant cells. Interestingly, a panel of specific and effective inhibitors of CK2 is available, and several examples are known of their efficacy in resistant cells, with synergistic effect when used in combination with conventional drugs, also in vivo. Here we analyze and discuss evidences supporting the hypothesis that CK2 targeting represents a valuable strategy to overcome drug resistance.

After the development of accelerators as neutron source, the access to new suitable agents for boron neutron capture therapy (BNCT) became a major need. Among many others, sugar boronic acids have recently attracted attention as boron carriers. Herein we report the synthesis and preliminary biological studies of two new sugar analogues containing a boronic acid at the anomeric position. The analogues were obtained by hydroboration of proper open-chain terminal alkenes that, after quenching with water, spontaneously afforded cyclic boronic acids with hemiacetal-like structures.

Abstract RGD‐cryptophycin and isoDGR‐cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin‐binding antimitotic agent across lysosomally cleavable Val‐Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin αvβ3, showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21‐L with different expression levels of integrin αvβ3, showing nanomolar potency of all four compounds against both cell lines. Conjugates containing uncleavable linker show reduced activity compared to the corresponding cleavable conjugates, indicating efficient intracellular drug release in the case of cryptophycin‐based SMDCs. However, no significant correlation between the in vitro biological activity of the conjugates and the integrin αvβ3 expression level was observed, which is presumably due to a non‐integrin‐mediated uptake. This reveals the complexity of effective and selective αvβ3 integrin‐mediated drug delivery.

Triphenyltin(IV) compounds with naphthoquinone derivatives containing N-acetylcysteine, N-acetyl-S-(1,2-dion-4-naphthyl)cysteine (1,2-NQC), 1, and N-acetyl-S-(1,4-dion-2-naphthyl)cysteine (1,4-NQC), 2, were synthesized and characterized by elemental microanalysis, IR, multinuclear (1H, 13C, 119Sn) NMR spectroscopy as well as HR-ESI mass spectrometry. With the aim of in vitro anticancer activity determination of ligand precursors and novel synthesized organotin(IV) compounds against human cervix adenocarcinoma (HeLa), human colon carcinoma (HT-29), and melanoma carcinoma cell line (B16F10), MTT colorimetric assay method was applied. The results indicate that synthesized compounds exhibited remarkable antiproliferative activity toward all tested cell lines with IC50 in the range of 0.17 to 0.87 μM. Complex 1 showed the greatest activity against HT-29 cells, with IC50 value of 0.21 ± 0.01 μM, 119 times better than cisplatin, while complex 2 demonstrated the highest activity toward HeLa cells, IC50 = 0.17 ± 0.01 μM, which is ~26 times better than cisplatin. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172035]

Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical stability, and synthetic feasibility. In our quest towards the development of novel scaffolds for effective vascular endothelial growth 2 (VEGFR-2) inhibition with antiangiogenic activity, four novel series of pyridazines were designed and synthesised. Five of the synthesised compounds; namely (8c, 8f, 15, 18b, and 18c) exhibited potent VEGFR-2 inhibitory potency (>80%); with IC50 values ranging from low micromolar to nanomolar range; namely compounds 8c, 8f, 15, 18c with (1.8 µM, 1.3 µM, 1.4 µM, 107 nM), respectively. Moreover, 3-[4-{(6-oxo-1,6-dihydropyridazin-3-yl)oxy}phenyl]urea derivative (18b) exhibited nanomolar potency towards VEGFR-2 (60.7 nM). In cellular assay, the above compounds showed excellent inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells at 10 μM concentration. Finally, an extensive molecular simulation study was performed to investigate the probable interaction with VEGFR-2.

Background: The chemistry and applications of 2-pyridone structures have recently attracted a lot of attention due to their uses as synthetic intermediates and their biological importance. Furthermore, 2-pyridones are a different category of pharmacophores that exhibit several biological activities. Results: The 2-pyridones substrates are synthetically multilateral, where they can be used to synthesize a wide range of heterocyclic compounds and as a drug synthesis raw material. Therefore, it was the purpose of this review to evaluate the pharmacological properties of various substituted 2-pyridone systematically and collates these findings to be used as a guide for future structure–activity relationship and mode of action studies. Conclusion: Taken together, we demonstrate that the fused 2-pyridone is a versatile scaffold for biological applications.

A cyclometalated IrIII complex conjugated to a far‐red‐emitting coumarin, IrIII‐COUPY (3), was recently shown as a very promising photosensitizer suitable for photodynamic therapy of cancer. Therefore, the primary goal of this work was to deepen knowledge on the mechanism of its photoactivated antitumor action so that this information could be used to propose a new class of compounds as drug candidates for curing very hardly treatable human tumors, such as androgen resistant prostatic tumors of metastatic origin. Conventional anticancer chemotherapies exhibit several disadvantages, such as limited efficiency to target cancer stem cells (CSCs), which are considered the main reason for chemotherapy resistance, relapse, and metastasis. Herein, we show, using DU145 tumor cells, taken as the model of hormone‐refractory and aggressive prostate cancer cells resistant to conventional antineoplastic drugs, that the photoactivated conjugate 3 very efficiently eliminates both prostate bulk (differentiated) and prostate hardly treatable CSCs simultaneously and with a similar efficiency. Notably, the very low toxicity of IrIII‐COUPY conjugate in the prostate DU145 cells in the dark and its pronounced selectivity for tumor cells compared with noncancerous cells could result in low side effects and reduced damage of healthy cells during the photoactivated therapy by this agent. Moreover, the experiments performed with the 3D spheroids formed from DU145 CSCs showed that conjugate 3 can penetrate the inner layers of tumor spheres, which might markedly increase its therapeutic effect. Also interestingly, this conjugate induces apoptotic cell death in prostate cancer DU145 cells associated with calcium signaling flux in these cells and autophagy. To the best of our knowledge, this is the first study demonstrating that a photoactivatable metal‐based compound is an efficient agent capable of killing even hardly treatable CSCs. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel AuIII cyclometalated prodrugs of energy‐disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated AuIII fragment. The lead complex 3met was 6000‐fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro‐survival responses to induce deadly metabolic catastrophe. [ABSTRACT FROM AUTHOR]

Due to their unique ability to actively move, micro/nanomotors offer the possibility of breaking through the limitations of traditional passive drug delivery systems for the treatment of many diseases, and have attracted the increasing attention of researchers. However, at present, the realization of many advantages of micro/nanomotors in disease treatment in vivo is still in its infancy, because of the complexity and particularity of diseases in different parts of human body. In this Minireview, we first focus on the biosafety and functionality of micro/nanomotors as a biomedical treatment system. Then, we address the treatment difficulties of various diseases in vivo (such as ophthalmic disease, orthopedic disease, gastrointestinal disease, cardiovascular disease, and cancer), and then review the research progress of biomedical micro/nanomotors in the past 20 years, Finally, we propose the challenges in this field and possible future development directions [ABSTRACT FROM AUTHOR]

An emerging approach in the field of targeted drug delivery is the establishment of abiotic metal‐triggered prodrug mechanisms that can control the release of bioactive drugs. Currently, the design of prodrugs that use abiotic metals as a trigger relies heavily on uncaging strategies. Here, we introduce a strategy based on the gold‐catalyzed activation of a phenanthridinium‐based prodrug via hydroamination under physiological conditions. To make the prodrug strategy biocompatible, a gold artificial metalloenzyme (ArM) based on human serum albumin, rather than the free gold metal complex, was used as a trigger for prodrug activation. The albumin‐based gold ArM protected the catalytic activity of the bound gold metal even in the presence of up to 1 mM glutathione in vitro. The drug synthesized via the gold ArM exerted a therapeutic effect in cell‐based assays, highlighting the potential usefulness of the gold ArM in anticancer applications. [ABSTRACT FROM AUTHOR]

Cancer is the world's biggest global health concern. The prevalence and mortality rates of cancer remain high despite significant progress in cancer therapy. The search for more effective, as well as less toxic treatment methods for cancer, is at the focus of current studies. Approximately 24.6 million people are suffering from cancer across the world as per the world health organization (WHO). In the year 2020, approximately 10 million deaths were reported due to cancer which has emerged as the second leading cause of mortality across the globe. Anticancer medicines have played a pivotal role in the medication of different types of cancers; however, they are associated with several side effects and relevance of drug resistance which evoke an immediate need for designing of new anticancer agents with multitargeted effect. Imidazole is a heterocyclic compound privileged with considerable anticancer activities and some imidazole derivatives have already got approval to treat cancer. Many hybrid molecules are available that play an important role in the treatment of cancer like chalcone, pyrazole, purine, triazine etc., and their pharmacophore provide the anticancer drug with low drug resistance and high efficacy, with low chances of toxicity and side effects. This review provides various approaches for the drug development of new safe and efficient antitumor agents imidazole hybrids with other heterocyclic moieties. An attempt has been made to advancement of the anticancer potential of the derivatives and hybrids of imidazole having intact or condensed imidazole moiety in the last decade along with the structure‐activity relationship studies, and mechanism of action. [ABSTRACT FROM AUTHOR]

Two new Drug Delivery Systems (DDS) cyclo[DKP-isoDGR]-PEG-4-Val-Ala-PTX (2) and cyclo[DKP-isoDGR]-PEG-4-sC18-Val-Ala-PTX (3), containing the cyclo[DKP-isoDGR] integrin ligand and the cytotoxic agent Paclitaxel (PTX), were synthesized to investigate the influence of a PEG-4 chain and of the sC18 cell-penetrating peptide (CPP) on the cellular uptake and the cytotoxicity of the constructs. A "double click-reaction strategy" was planned, to realize the connection of cyclo[DKP-isoDGR] and PTX to the CPP moiety. Anti-proliferative bioassays were performed on the αvβ3-positive U87 human glioblastoma cell line using a short contact time (15 min) followed by draining, washing of the cells, and re-incubation for 72 h. Compound 3 was significantly more potent (IC50=27.6 µM) than compound 2 (IC50>100 µM), and showed a reduced potency loss with respect to PTX (IC50=71 nM). [ABSTRACT FROM AUTHOR]

Iron(III) complexes of curcumin (Hcur) having a tridentate NNNdonor dipicolylamine-based ligand L¹ and its biotinylated analogue L², namely, [Fe(L¹)(cur)Cl] (1) and [Fe(L²)(cur)Cl] (2), were prepared, characterized and their photo-induced cytotoxicity studied. The complexes exhibited curcumin-based absorption band near 430 nm and emission maxima at 520 nm. Complex 2 with a biotin moiety showed enhanced cellular uptake and higher cytotoxicity compared to its non-biotin analogue 1. The visible light induced cytotoxicity was studied in HeLa, MCF-7 and HepG2 cell lines. Complex 2 displayed photodynamic effect (400-700 nm, 10 Jcm-2) giving an IC50 value of ~4 μM in HeLa and MCF-7 cells, while being significantly nontoxic in the dark (IC50>100 μM). A 5-fold increase in cytotoxicity was observed in HepG2 cells (IC50~0.7 μM) for the biotinappended complex 2. In vitro generation of reactive oxygen species (ROS) was observed from dichlorofluorescein diacetate (DCFDA) assay. The mode of cell death was apoptotic. Formation of hydroxyl radicals as the ROS was evidenced from the plasmid pUC19 DNA photo-cleavage studies. The complexes demonstrated the ability to act as targeted PDT (photodynamic therapy) drugs. [ABSTRACT FROM AUTHOR]

Fourteen new RuII–arene (p‐cymene/benzene) complexes (C1–C14) have been synthesized by varying the N‐terminal substituent in the furoylthiourea ligand and satisfactorily characterized by using analytical and spectroscopic techniques. Electrostatic potential maps predicted that the electronic effect of the substituents was mostly localized, with some influence seen on the labile chloride ligands. The structure–activity relationships of the Ru–p‐cymene and Ru–benzene complexes showed opposite trends. All the complexes were found to be highly toxic towards IMR‐32 cancer cells, with C5 (Ru–p‐cymene complex containing C6H2(CH3)3 as N‐terminal substituent) and C13 (Ru–benzene complex containing C6H4(CF3) as N‐terminal substituent) showing the highest activity among each set of complexes, and hence they were chosen for further study. These complexes showed different behavior in aqueous solutions, and were also found to catalytically oxidize glutathione. They also promoted cell death by apoptosis and cell cycle arrest. Furthermore, the complexes showed good binding ability with the receptors Pim‐1 kinase and vascular endothelial growth factor receptor 2, commonly overexpressed in cancer cells. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: Lithocarpins E—G, featuring a rare naturally‐occurring highly oxygenated tenellone‐macrolide skeleton, were isolated from the culture extract of a marine‐derived fungus Phomopsis lithocarpus FS508. Their structures were fully elucidated by NMR and MS spectroscopic analyses and electronic circular dichroism calculations. Compounds 1—3 were evaluated for their in vitro cytotoxicities against HepG2, MCF‐7, SF‐268, as well as A549 cell lines, among which, compound 1 exhibited inhibitory activity against HepG2 cells with an IC50 value of 6.3 μmol/L. The further mechanistic investigation demonstrated that lithocarpin E could cause the apoptosis of HepG2 cells through activation of p‐ERK, Bax, and caspase‐3 gene expressions. [ABSTRACT FROM AUTHOR]

In the present study, synthesis of a simple series of nitrogen heterocycles containing N-(pbromophenyl) carboxamide moiety, such as benzimidazole, benzoxazine, oxadiazole and triazole compounds, by using 4-bromo aniline and diethyl oxalate as a key starting material has been described. Five nitrogen heterocycles compounds moiety were evaluated for their anticancer activity against MCF-7 cell line. The results revealed that compound 8 (N-(4-bromophenyl)-5-thioxo-1,3,4-oxadiazole-2-carboxamide) was the most potent cytotoxic activity. Cell cycle analysis demonstrated that compound 8 induce cell cycle arrest at G1 phase with apoptosis inducing activity marked by increase in G0 phase. [ABSTRACT FROM AUTHOR]

Exploring the potential of bis(thiosemicarbazones) (BTSC), a new family of BTSC ligands derived from GTSM (glyoxal-bis(N4- methylthiosemicarbazonato) and respective CuIIBTSC complexes were synthesized. These complexes, having pendant nitrogen heterocycles, exhibited increased water-solubility, lower lipophilicity at physiological pH and more negative Cu(II)/Cu(I) redox potential, when compared with the parental complex. The cytotoxic evaluation performed in a panel of cancer cells lines showed an important effect of the metal complexation, and furthermore correlated well with the cellular uptake of the compounds, which was determined using their 64Cu congeners. The radiolabelling of the complexes also allowed more detailed uptake studies, with the results suggesting an active transport or facilitated diffusion mechanism for the cellular uptake of 64CuGTSMpip and 64CuGTSMmor, with pendant piperidine and morpholine rings, respectively. Additionally, a comparative study with the corresponding Cu(II) complexes derived from ATSM (diacetyl-bis(NU4-methylthiosemicarbazonato) that we have previously described, demonstrated a clear difference in their lysosomotropic properties in particular for the piperidine derivatives. From this study, CuGTSMpip emerged as the most promising compound to be further evaluated as an anticancer metallodrug. [ABSTRACT FROM AUTHOR]

A panel of 1,3-diynyl-noscapinoids (20–22) were strategically designed to increase the anticancer activity of the lead molecule, noscapine. Structure-activity analyses revealed strong predicted free energy of binding (ΔGbind,pred) of 6.694, 7.294 and 7.468 kcal/mol, for 20–22 respectively compared to noscapine (experimental free energy of binding (ΔGbind,expt) is 5.246 kcal/mol). These novel derivatives were demonstrated to bind tubulin by fluorescence quenching assay and Far-UV circular dichroism. Further, they were tested to exhibit potent cytotoxic activity compared to noscapine using two human breast cancer cell lines. The IC50 value for noscapine, 20, 21 and 22 has been derived to be 35.2, 27.3, 18.7 and 12.7 μM using MCF7 and 39.6, 31.4, 22.5 and 16.1 μM using MDAMB-231. These derivatives were found to arrest cell cycle in the G2/Mphase followed by apoptosis and appearance of TUNEL-positive cells. Thus, we conclude that 1,3-diynyl derivatives of noscapine have great potential to be a novel therapeutic agent for breast cancers. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) is a rare subtype of cancer, with a poor prognosis in children and adults. Mitotane is the only approved adrenolytic drug for the treatment of ACC, which has controversies regarding its efficacy and side effects on patients. Onion (Allium cepa), a worldwide consumed food, is associated with many health benefits. Along with its glycosides, the flavonoid quercetin is abundant in onions. After evaluating the cytotoxicity of A. cepa extracts on adrenocortical carcinoma cell line (H295R), the rich quercetin fractions had better results. Then, we aimed to compare the quercetin vs. mitotane effectiveness, using adrenocortical carcinoma cell lines H295R and SW-13. Quercetin showed a higher cytotoxicity response on both cancerous cell lines after 10 µM concentration, while mitotane only after 30 µM. Cell cycle dynamics were altered upon quercetin treatments, with G2 phase increase with 30 µM of quercetin on H295R cell line and G1 arrest on SW-13 cell line with 15 µM. Early and late apoptosis, alongside intracellular calcium, were increased on SW-13 treated with 30 µM of quercetin, and ROS rates were reduced by quercetin on H295R. Therefore, quercetin-rich onions have the potential to be a natural source of anticancer agents for adrenocortical carcinoma.

Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study.

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry.

Lewis acid‐catalyzed [6+1] annulation reactions of 2‐cyano‐1‐propargyl‐ and 2‐alkynyl‐1‐cyanomethyl‐indoles with Reformatsky reagent are described. 8‐Aryl, 8‐alkyl‐, 8‐hetaryl‐, 9‐aryl, and 9‐alkyl‐azepino[1,2‐a]indole amines were obtained through a 7‐endo‐mode cyclization of the β‐aminoacrylate intermediates. The antiproliferative activity of the azepino[1,2‐a]indoles analogs against the HCT‐116 cells were also examined. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) involves the catalytic generation of highly toxic hydroxyl radicals (.OH) from hydrogen peroxide (H2O2) through metal‐ion‐mediated Fenton or Fenton‐like reactions. Fe2+ is a classical catalyst ion, however, it suffers easy oxidation and systemic side‐effects. Therefore, the development of a controllable Fe2+ delivery system is a challenge to maintain its valence state, reduce toxicity, and improve therapeutic efficacy. Reported here is a near‐infrared (NIR) light‐triggered Fe2+ delivery agent (LET‐6) for fluorescence (FL) and photoacoustic (PA) dual‐modality imaging guided, photothermal primed CDT. Thermal expansion caused by 808 nm laser irradiation triggers the transformation of LET‐6 to expose Fe2+ from its hydrophobic layer, which primes the catalytic breakdown of endogenous H2O2 within the tumor microenvironment, thus generating.OH for enhanced CDT. LET‐6 shows remarkable therapeutic effects, both in vitro and in vivo, achieving 100 % tumor elimination after just one treatment. This high‐performance Fe2+ delivery system provides a sound basis for future synergistic metal‐ion‐mediated cancer therapy. [ABSTRACT FROM AUTHOR]