Camptothecin Derivatives Research Articles

Design and synthesis of novel 7-ethyl-10-fluoro-20-O-(cinnamic acid ester)-camptothecin derivatives as potential high selectivity and low toxicity topoisomerase I inhibitors for hepatocellular carcinoma

A series of new 7-ethyl-10-fluoro-20-O-(cinnamic acid ester)-camptothecin derivatives were synthesized and evaluated for cytotoxicity against four human tumor cell lines including HepG2 (hepatocellular carcinoma), SW480 (colorectal cancer), A2780 (ovarian cancer), and Hucct1 (intrahepatic cholangiocarcinoma). The results of cytotoxic activities in vitro showed that most of the camptothecin derivatives harbor promising cytotoxic activity against tested tumor cell lines. Among them, compound XJS-11 exhibited broad-spectrum inhibitory activities against HepG2, SW480, A2780, and Hucct1 cell lines with IC50 values of 0.03, 0.09, 0.22, and 0.32 μM, respectively. Further investigation demonstrated that compound XJS-11 exhibited more effective growth inhibition against a variety of human hepatoma cells (Sk-hep-1, Hep3B and Huh7) and lower cytotoxicity against immortalized normal human liver cell line L02 than the positive control topotecan. Especially, XJS-11 showed higher selective toxicity in two kinds of human hepatoma cells and immortalized normal human liver cell line (IC50(L-02)/IC50(HepG2) = 113.20; IC50(L-02)/IC50(Hep3B) = 85.60) than topotecan (IC50(L-02)/IC50(HepG2) = 9.45; IC50(L-02)/IC50(Hep3B) = 8.52). Mechanistically, XJS-11 induced cell cycle arrest and cell apoptosis in HepG2 and Hep3B cells by inhibiting Top I activity in a manner similar to that of topotecan. Meanwhile, XJS-11 could attenuate the tumor growth in both xenograft and primary HCC mouse models. In addition, the acute toxicity assay showed that XJS-11 did not cause lethality or significant body weight loss with a single intraperitoneal dose at 100 mg/kg or with an intraperitoneal dose at 25 mg/kg for 7 days. Moreover, unlike topotecan, XJS-11 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the C57BL/6 mice. Taken together, XJS-11 merits further development as a new generation of the camptothecin-derived drug candidate.

TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor.

Exatecan and deruxtecan are antineoplastic camptothecin derivatives in development as tumor-targeted-delivery warheads in various formulations including peptides, liposomes, polyethylene glycol nanoparticles, and antibody-drug conjugates. Here, we report the molecular pharmacology of exatecan compared with the clinically approved topoisomerase I (TOP1) inhibitors and preclinical models for validating biomarkers and the combination of exatecan with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitors. Modeling exatecan binding at the interface of a TOP1 cleavage complex suggests two novel molecular interactions with the flanking DNA base and the TOP1 residue N352, in addition to the three known interactions of camptothecins with the TOP1 residues R364, D533, and N722. Accordingly, exatecan showed much stronger TOP1 trapping, higher DNA damage, and apoptotic cell death than the classical TOP1 inhibitors used clinically. We demonstrate the value of SLFN11 expression and homologous recombination (HR) deficiency (HRD) as predictive biomarkers of response to exatecan. We also show that exatecan kills cancer cells synergistically with the clinical ATR inhibitor ceralasertib (AZD6738). To establish the translational potential of this combination, we tested CBX-12, a clinically developed pH-sensitive peptide-exatecan conjugate that selectively targets cancer cells and is currently in clinical trials. The combination of CBX-12 with ceralasertib significantly suppressed tumor growth in mouse xenografts. Collectively, our results demonstrate the potency of exatecan as a TOP1 inhibitor and its clinical potential in combination with ATR inhibitors, using SLFN11 and HRD as predictive biomarkers.

Mini Review on Some African Plants with Anti-Cancer Properties

Every year, cancer takes the life of millions of people. Indeed, medicinal plants have long been investigated by scientists for their anti-cancer properties. Herbal plants have recently attracted worldwide attention of researchers for their possible use in the management of diseases such as diabetes, cardiovascular diseases, cancer, and respiratory diseases. Most of the conventional cancer treatment options have produced unsatisfactory results for some types of cancers, and in most instances, the side effects are severe, leading to a shift in the focus of treatment towards alternative medicines. Plant-derived compounds have been a vital source of most of the known clinically useful anti-cancer agents. These include vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, etoposide, derived from epipodophyllotoxin, and paclitaxel (taxol®), taxanes, homoharringtonine and elliptinium. Many promising new agents are in clinical development based on selective activity against cancer-related molecular targets. African plants have a vital role in cancer chemoprophylaxis and chemotherapy. With advanced knowledge of molecular science and refinement in isolation and structure elucidation techniques, various African plants with anticancer properties have been identified,and some of which exert their therapeutic effects by inhibiting cancer-activating enzymes and hormones, stimulating DNA repair mechanism, promoting production of protective enzymes, inducing antioxidant action or enhancing natural immunity of the individual. This review attempts to examine scientific information in the available literature on some specific African plants with anti-cancer properties.

9-Nitro-20(S)-carbonate-camptothecin (NCP4), a novel prodrug of 9-nitrocamptothecin (9-NC), exhibits potent chemotherapeutic efficacy and improved safety against hepatocarcinoma

9-nitrocamptothecin (9-NC), an active derivative of camptothecin (CPT), demonstrated antitumor effect on experimental tumors in mice by topoisomerase I (Topo I) inhibition. However, under human physiological conditions, the rapid opening of lactone ring of 9-NC resulting in the formation of inactive and high toxic carboxylate limited its clinical efficacy. Therefore, strategies aimed to maintain the active closed-lactone form of 9-NC in the plasma were developed, such as prodrugs. In our study, 9-nitro-20(S)-carbonate-camptothecin (NCP4), a novel prodrug of 9-NC, was designed and synthesized. A preclinical evaluation of the chemotherapeutic potential of NCP4 was performed in vitro and in vivo. In cytotoxicity assay against six human cancer cells, the cytotoxic effect of NCP4 was slightly weaker than 9-NC. In addition, our data showed that 9-NC can be converted from NCP4 in vivo, and that the intracellular conversion of NCP4 to its active metabolites was correlated well with its cytotoxicity, demonstrating that NCP4 could serve as a prodrug of 9-NC. In human hepatoma Bel-7402 xenografts, NCP4 by intravenous injection showed more potent antitumor efficacy than 9-NC. Mechanistically, NCP4 induced cell apoptosis by increasing the expressions of caspase-3 and Bax in tumor tissues. In human hepatoma Hep G2 xenografts, NCP4 by oral administration significantly inhibited tumor growth. Importantly, the toxic effect of NCP4 on mice was much lower than 9-NC, demonstrating improved safety of NCP4. Overall, our study indicated that NCP4 would be a promising anticancer candidate and worthy of further investigation.

Poloxamer-linked prodrug of a topoisomerase I inhibitor SN22 shows efficacy in models of high-risk neuroblastoma with primary and acquired chemoresistance.

High‐risk solid tumors continue to pose a tremendous therapeutic challenge due to multidrug resistance. Biological mechanisms driving chemoresistance in high‐risk primary and recurrent disease are distinct: in newly diagnosed patients, non‐response to therapy is often associated with a higher level of tumor “stemness” paralleled by overexpression of the ABCG2 drug efflux pump, whereas in tumors relapsing after non‐curative therapy, poor drug sensitivity is most commonly linked to the dysfunction of the tumor suppressor protein, p53. In this study, we used preclinical models of aggressive neuroblastoma featuring these characteristic mechanisms of primary and acquired drug resistance to experimentally evaluate a macromolecular prodrug of a structurally enhanced camptothecin analog, SN22, resisting ABCG2‐mediated export, and glucuronidation. Together with extended tumor exposure to therapeutically effective drug levels via reversible conjugation to Pluronic F‐108 (PF108), these features translated into rapid tumor regression and long‐term survival in models of both ABCG2‐overexpressing and p53‐mutant high‐risk neuroblastomas, in contrast to a marginal effect of the clinically used camptothecin derivative, irinotecan. Our results demonstrate that pharmacophore enhancement, increased tumor uptake, and optimally stable carrier‐drug association integrated into the design of the hydrolytically activatable PF108‐[SN22]2 have the potential to effectively combat multiple mechanisms governing chemoresistance in newly diagnosed (chemo‐naïve) and recurrent forms of aggressive malignancies. As a macromolecular carrier‐based delivery system exhibiting remarkable efficacy against two particularly challenging forms of high‐risk neuroblastoma, PF108‐[SN22]2 can pave the way to a robust and clinically viable therapeutic strategy urgently needed for patients with multidrug‐resistant disease presently lacking effective treatment options.

Enhanced synergistic antitumor efficacy with topotecan (camptothecin derivative) and curcumin analogs coadministration in novel proniosomal formulations

Background: In the modern era of therapeutics, the proniosomal system has been identified as the most intriguing one among various novel systems, thus considerably enhancing the bioavailability of low-soluble drugs. The current study aimed to study the enhancement of therapeutic efficacy of topotecan (TPT) with curcumin (CUR) coadministration. Materials and Methods: We optimized the preparation of niosomes, concerning concentrations of lecithin, span 60, and cholesterol. Seventeen trials were proposed by the selected design. All these batches were initially evaluated only for entrapment efficacy (EE), vesicle size (VS), and percentage of TPT release by the end of 12 h. Analysis of variance and generated regression equations were assisted to study the significant variables and magnitude of impact. Results: The desirability of 0.893 was achieved with the optimum concentrations of selected independent variables in attaining the highest EE (90.393%), minimum VS (386.264 nm), and percentage of TPT release (98.614% at 12 h). TPT and CUR release from the optimized formulation were found to be anomalous or non-Fickian diffusion, as evident from the n value of Peppas model. The cytotoxic studies demonstrated that TPT and CUR in liposomal and free forms were found to be less cytotoxic on MCF-7 model cells. All these findings indicate that the coadministration of CUR with TPT proniosomes can be a promising strategy to enhance the antitumor treatment.

On-Demand Activation of a Bioorthogonal Prodrug of SN-38 with Fast Reaction Kinetics and High Releasing Efficiency In Vivo.

Although a myriad of bioorthogonal prodrugs have been developed, very few of them present both fast reaction kinetics and complete cleavage. Herein, we report a new bioorthogonal prodrug strategy with both fast reaction kinetics (k2: ∼103 M-1 s-1) and complete cleavage (>90% within minutes) using the bioorthogonal reaction pair of N-oxide and boron reagent. Distinctively, an innovative 1,6-elimination-based self-immolative linker is masked by N-oxide, which can be bioorthogonally demasked by a boron reagent for the release of both amino and hydroxy-containing payload in live cells. Such a strategy was applied to prepare a bioorthogonal prodrug for a camptothecin derivative, SN-38, resulting in 10-fold weakened cytotoxicity against A549 cells, 300-fold enhanced water solubility, and "on-demand" activation upon a click reaction both in vitro and in vivo. This novel bioorthogonal prodrug strategy presents significant advances over the existing ones and may find wide applications in drug delivery in the future.

Camptothecin derivatives induce apoptosis and inhibit proliferation of prostate cancer PC-3M cells through downregulation of PI3K/Akt signaling pathway

• Synthesis of novel camptothecin derivatives. • All compounds showed good in vitro cytotoxicity against five tumour cell lines. • 3D-QSAR, molecular docking to explore conformational relationships. Malignant tumors are increasing the human mortality rate year by year, so there is an urgent need to develop novel and highly effective drugs. Camptothecin (CPT) is a natural medicinal product with broad-spectrum antitumor activity. In this study, 11 CPT derivatives were synthesized. Their antitumor activities were evaluated by CCK-8, morphological observation, plate cloning, scratching, DAPI staining, cell cycle, and apoptosis. The conformational relationships were also analyzed by molecular docking and 3D-QSAR. The results showed that the CPT derivatives showed significant inhibitory effects on all five tumor cell lines, A549, HepG2, MCF-7, HemECs, and PC-3M, with the best inhibitory ability against PC-3M in prostate cancer. Among all derivatives, compound 5 had the lowest IC50 value of 0.0881 μM. In addition, compound 5 regulated the downstream cascade response by inhibiting the PI3K-Akt signaling pathway, causing cycle arrest and apoptosis. The predicted results of molecular docking and 3D-QSAR were consistent with those of the experimental group. This demonstrates the anti-tumor potential of compound 5.

Curcumin protects against testis-specific side effects of irinotecan.

Irinotecan (IR/CPT-11) is a semisynthetic, water-soluble derivative of the alkaloid camptothecin. It is a topoisomerase I group antineoplastic drug commonly used for the treatment of many cancer types, although it has side effects in tissues such as the testis. Curcumin (CRC) is a polyphenol compound produced from the Indian saffron root; it is used as food colouring and food flavouring. This study examined the testis-specific side effects of IR and the ability of CRC to protect against these side effects. Forty male Sprague-Dawley rats were used in our study (n = 10). The rats were randomly divided into the following four groups: control, IR, IR + CRC, and CRC. IR 10 mg/kg/day was administered intraperitoneally and CRC 100 mg/kg was administered orally. Blood and testicular samples were collected from rats in all four groups on day 30 after drug administration. Histological, biochemical, and spermatological analyses were conducted. Testis tissue and blood samples were collected from the four groups. Tissue samples from the control and CRC groups demonstrated normal histological appearance on light microscopy. The IR group exhibited the following findings: vascular congestion in the tunica albuginea layer; tubular degeneration and vascular congestion in the interstitial area; oedema, vacuolisation, and luminised cells in the seminiferous tubule; and cells that temporarily stopped dividing at any stage of division in the seminiferous tubule epithelium. In the IR+CRC group, histopathological damage was significantly reduced by CRC treatment. Biochemical analysis showed that the level of thiobarbituric acid reactive substance (TBARS) was significantly increased in the IR group, compared with the other groups. CRC treatment significantly decreased this IR-mediated increase in TBARS level, and the TBARS level in the IR + CRC group approached the level observed in the control group. IR treatment caused significant decreases in glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) levels. However, CRC administration tended to ameliorate the decreases in GSH, SOD, CAT, and GPx levels. In this study, IR had some toxic effects in rat testis tissue; these effects were ameliorated by CRC treatment. Further studies are warranted to confirm our results.

Discovering and harnessing oxidative enzymes for chemoenzymatic synthesis and diversification of anticancer camptothecin analogues

Semi-synthetic derivatives of camptothecin, a quinoline alkaloid found in the Camptotheca acuminata tree, are potent anticancer agents. Here we discovered two C. acuminata cytochrome P450 monooxygenases that catalyze regio-specific 10- and 11-oxidations of camptothecin, and demonstrated combinatorial chemoenzymatic C-H functionalizations of the camptothecin scaffold using the new enzymes to produce a suite of anticancer drugs, including topotecan (Hycamtin®) and irinotecan (Camptosar®). This work sheds new light into camptothecin metabolism, and represents greener approaches for accessing clinically relevant camptothecin derivatives.

Actions of Camptothecin Derivatives on Larvae and Adults of the Arboviral Vector Aedes aegypti.

Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and Onchocerca volvulus endanger health and economic security around the globe, and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of Aedes aegypti were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. We identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that reduced A. aegypti larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC50 of 25.5 ± 5.0 µM and 22.3 ± 5.4 µM, respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to A. aegypti adults at 100 µM and 10 µM, and completely blocked egg laying when fed at 100 µM. Camptothecin and its derivatives are inhibitors of topoisomerase I, have known activity against several agricultural pests, and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries.

PH-responsive and folate-coated liposomes encapsulating irinotecan as an alternative to improve efficacy of colorectal cancer treatment

Irinotecan (IRN) is a semisynthetic derivative of camptothecin that acts as a topoisomerase I inhibitor. IRN is used worldwide for the treatment of several types of cancer, including colorectal cancer, however its use can lead to serious adverse effects, as diarrhea and myelosuppression. Liposomes are widely used as drug delivery systems that can improve chemotherapeutic activity and decrease side effects. Liposomes can also be pH-sensitive to release its content preferentially in acidic environments, like tumors, and be surface-functionalized for targeting purposes. Herein, we developed a folate-coated pH-sensitive liposome as a drug delivery system for IRN to reach improved tumor therapy without potential adverse events. Liposomes were prepared containing IRN and characterized for particle size, polydispersity index, zeta potential, concentration, encapsulation, cellular uptake, and release profile. Antitumor activity was investigated in a murine model of colorectal cancer, and its toxicity was evaluated by hematological/biochemical tests and histological analysis of main organs. The results showed vesicles smaller than 200 nm with little dispersion, a surface charge close to neutral, and high encapsulation rate of over 90%. The system demonstrated prolonged and sustained release in pH-dependent manner with high intracellular drug delivery capacity. Importantly, the folate-coated pH-sensitive formulation had significantly better antitumor activity than the pH-dependent system only or the free drug. Tumor tissue of IRN-containing groups presented large areas of necrosis. Furthermore, no evidence of systemic toxicity was found for the groups investigated. Thus, our developed nanodrug IRN delivery system can potentially be an alternative to conventional colorectal cancer treatment.

Irinotecan and its metabolite SN38 inhibits procollagen I production of dermal fibroblasts from Systemic Sclerosis patients

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by a microangiopathy and fibrosis of the skin and internal organs. No treatment has been proved to be efficient in case of early or advanced SSc to prevent or reduce fibrosis. There are strong arguments for a key role of topo-I in the pathogenesis of diffuse SSc. Irinotecan, a semisynthetic derivative of Camptothecin, specifically target topo-I. This study was undertaken to evaluate the effects of noncytotoxic doses of irinotecan or its active metabolite SN38 on collagen production in SSc fibroblasts. Dermal fibroblasts from 4 patients with SSc and 2 healthy donors were cultured in the presence or absence of irinotecan or SN38. Procollagen I release was determined by ELISA and expression of a panel of genes involved in fibrosis was evaluated by qRT-PCR. Subcytotoxic doses of irinotecan and SN38 caused a significant and dose-dependent decrease of the procollagen I production in dermal fibroblasts from SSc patients, respectively − 48 ± 3%, p < 0.0001 and − 37 ± 6.2%, p = 0.0097. Both irinotecan and SN38 led to a global downregulation of genes involved in fibrosis such as COL1A1, COL1A2, MMP1 and ACTA2 in dermal fibroblasts from SSc patients (respectively − 27; − 20.5; − 30.2 and − 30% for irinotecan and − 61; − 55; − 50 and − 54% for SN38). SN38 increased significantly CCL2 mRNA level (+ 163%). The inhibitory effect of irinotecan and its active metabolite SN38 on collagen production by SSc fibroblasts, which occurs through regulating the levels of expression of genes mRNA, suggests that topoisomerase I inhibitors may be effective in limiting fibrosis in such patients.

Redox responsive 7-ethyl-10-hydroxycamptothecin (SN38) lysophospholipid conjugate: synthesis, assembly and anticancer evaluation

7-Ethyl-10-hydroxycamptothecin (SN38), a potent camptothecin derivative specifically targeting DNA topoisomerase I cleavage complexes, has shown great potential in the treatment of solid tumors. Because of its poor solubility and chemical and metabolic stability, the clinical application of SN38 is highly limited. To address these problems, a novel redox-responsive SN38 conjugate based liposomal formulation is developed in this report. First, SN38 was conjugated with lysophospholipid by using a cleavable disulfide bond linker. After that, the conjugate (SN38-SS-PC) was assembled into liposomes by thin film method. Dynamic lightscattering(DLS) characterization indicated that SN38-SS-PC liposomes possessed a narrow size distribution (172.8 ± 10.5 nm) and negative charged zeta potential (-8.9 ± 0.3 mV). The results of storage and physiological stabilities showed that SN38-SS-PC liposomes was stable under different conditions. More importantly, a reduction responsive release of parent drug SN38 was observed in the medium containing glutathione (GSH). In addition, SN38-SS-PC liposomes had a much more rapid cellular uptake behavior against cancer cells. The enhanced anti-cancer efficacy of SN38-SS-PC liposomes was further demonstrated by in vitro cytotoxicity assay against MCF-7 and A549 cells. Under in vivo evaluation in 4 T1 xenograft tumor model, SN38-SS-PC liposomes were observed to have lower systemic toxicity and higher tumor inhibition rate of 53.3% compared with the commercialized SN38 prodrug Irinotecan (Ir). In summary, SN38-SS-PC liposomes could be a promising redox responsive delivery system of SN38 for cancer therapy.

Plant-microbe interactions implicated in the production of camptothecin – An anticancer biometabolite from Phyllosticta elongata MH458897 a novel endophytic strain isolated from medicinal plant of Western Ghats of India

Endophytic wild fungal strain Phyllosticta elongata MH458897 isolated from medicinal plant Cipadessa baccifera from the Western Ghats region of Sathyamangalam Tiger Reserve Forest. This endophytic fungus has potential of effective anticancer drug Camptothecin (CPT). Endophytic fungi act as key symbionts in-between plants and ecosystem in the biosphere. This recently identified microbial population inside the plants produces many defence metabolites against plant pathogens. Among these defense metabolites, CPT gained much attention because of its effective anticancer activity. The maximum yield of CPT produced by optimizing the various factors like DEKM07 medium, pH 5.6, incubation time using Response Surface Methodology based on Central Composite Design. Extracted CPT is characterized using High Performance Liquid Chromatography and Electrospray ionization-Mass spectrometry. The highest yield of CPT was 0.747 mg/L was produced at optimized factors of dextrose – 50 g L−1, peptone – 5.708 g L−1, magnesium sulphate – 0.593 g L−1, and incubation time – 14 days. In-vitro MTT assay revealed the CPT derivatives were cytotoxic to A-549 cancer cell line (IC50 58.28 μg/ml) as nearly compared to the (IC50 51.08 μg/ml) standard CPT. CPT producing strain P. elongata from C. baccifera has the potential of CPT biosynthesis, and could be an effective anticancer bio metabolite. This compound has been described in the literature to be an effective anticancer metabolite. Our findings support the novel lifesaving anticancer drug from endophytic fungus in forest ecosystem concludes effective utilization of key symbionts will safeguard the humans and forest ecosystem.

Abstract 1182: The NEDD8 inhibitor pevonedistat blocks the repair of topoisomerase I (TOP1)-induced replication damage and synergizes with TOP1 inhibitors

Abstract Genomic DNA is constantly challenged by various genotoxic substances, resulting in an array of DNA lesions including DNA-protein crosslinks (DPCs), one of the most detrimental forms of DNA damage. Topoisomerase I (TOP1) is the molecular target of anti-cancer agents camptothecin derivatives and indenoisoquinolines, which act by trapping TOP1 on genomic DNA. The resulting TOP1-DPCs interfere with DNA replication and transcription and trigger cell death if left unrepaired. In this work, we found that the ubiquitin-like protein NEDD8 plays a pivotal role in the repair of TOP1-DPCs by activating the cullin 4 (CUL4)-RING ubiquitin ligases (CRL4) for K48-linked polyubiquitylation of TOP1-DPCs and their subsequent proteasomal degradation. We identified DCAF13, an understudied family member of DDB1- and CUL4-asscoiated factors, as the receptor of TOP1-DPCs for CRL4. DCAF13 colocalizes with TOP1-DPCs at nascent replication forks and binds the TOP1 core domain with its WD40 domains, linking TOP1 to DDB1-CRL4 for ubiquitylation upon TOP1-induced replication damage. Prompted by these findings, we hypothesized that targeting this NEDD8-activated repair pathway can be developed as a strategy to overcome resistance to TOP1 inhibitors. To test this hypothesis, we performed pharmacological analyses using CellMiner (http://discover.nci.nih.gov/cellminercdb) and found that the activities of TOP1 inhibitors and pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor in clinical trial, are highly correlated across cancer cell lines and with the expression of SLFN11. We also assessed the sensitivity of cultured cancer cells to combination of clinical TOP1 inhibitors and pevonedistat. The combination exhibited synergy in multiple cell lines particularly in human colon cancer cells HCT116 independently of SLFN11. We next investigated the efficacy of combination with TOP1 inhibitor topotecan and pevonedistat in HCT116 xenografts and observed supra-additive effect on tumor growth inhibition. Taken together, our work not only identifies a novel pathway for the repair of TOP1-DPCs but also provides translational evidence to support pevonedistat in combination with TOP1 inhibitors as a rationale therapeutic combination for cancer treatments. Citation Format: Yilun Sun, Andrea Baechler, Valentina Factor, Kanako Okamoto, Yves Pommier. The NEDD8 inhibitor pevonedistat blocks the repair of topoisomerase I (TOP1)-induced replication damage and synergizes with TOP1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1182.

Abstract 1314: A novel small molecule drug conjugate -avb3 integrin antagonist linked to a cytotoxic camptothecin derivative- for the treatment of multiple cancer types

Abstract To improve tumor selectivity of cytotoxic agents we designed small molecule drug conjugates leveraging two independent mechanisms of targeted delivery by utilizing an integrin binder for tumor homing and release of the active drug by proteases present in tumor stroma. Integrins are transmembrane receptors that mediate cell-extracellular matrix and cell-cell interaction. αvβ3 integrins in the tumor microenvironment are involved in critical events for tumor progression, cytotoxic therapy resistance and metastasis including angiogenesis, matrix remodeling and the recruitment of immune and inflammatory cells. Proteases in tumor stoma such as neutrophil elastase also contribute to cancer progression by enhancing tumor evasion and metastasis. The expectation is that small molecule drug conjugates could have better efficacy for solid tumors than antibody drug conjugates due to better tissue penetration. Following this rationale the small molecule drug conjugate is composed of a peptidomimetic αvβ3 integrin antagonist linked to a cytotoxic camptothecin derivative via a linker susceptible to cleavage by neutrophil elastase. Imaging studies with the αvβ3 antagonist conjugated with an IR-800 dye demonstrated efficient tumor targeting to 786-0 renal adenocarcinoma tumors, as compared with a weakly binding epimer used as a control conjugate. The targeted conjugate is highly stable in rat plasma and shows strong cytotoxic activity only in the presence of neutrophil elastase. The payload displays high cellular permeability and in contrast to SN38, the active metabolite of irinotecan, it is not a substrate of efflux transporters. The conjugate is highly efficacious in vivo effecting tumor regressions in SW480 (colon cancer), MX1 (breast cancer) and NCI-H69 (lung cancer) xenograft models with T/C ratios of 0.1, 0.03 and 0.06 (p&amp;lt;0.05 each, compared to vehicle control) respectively and it shows very good tolerability. Initial pharmacokinetic studies in tumor bearing mice demonstrate a more than 10-fold improved tumor/plasma ratio of free toxophore when administered as a conjugate as compared with direct administration of unconjugated toxophore. In summary, our results show potent, selective, in vivo anticancer activity against three solid tumor subtypes with a novel small molecule drug conjugate consisting of the conjugation of an integrin antagonist with a cytotoxic agent via a tailored linker enabling cleavage in tumor stroma. Citation Format: Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Charlotte Kopitz, Melanie Heroult, Dmitry Zubov, Joerg Willuda, Thomas Schlange, Antje Kahnert, Raquel Izumi, Ahmed Hamdy. A novel small molecule drug conjugate -avb3 integrin antagonist linked to a cytotoxic camptothecin derivative- for the treatment of multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1314.

Biologically Active Substances and Extracts of Fungal Origin

Studying the biological activity of fungi is crucial to discovering their potential for the treatment and prevention of various diseases. The diverse composition and various substances they produce are the basis of their application in medicine. Pullulan can be used as blood plasma substituent, carrier in drug delivery systems. Chitin possess antimicrobial, anticoagulant and antitumor activities. Inotodiol and the other substances from Inonotus obliquus possess strong cytotoxic activity against breast and gastric cancer. Camptothecin derivatives are used for treatment of ovarian and colorectal cancers. In our study we used a strain Antarctic yeasts Cryptococcus laurentii AL65. We found out that these psychrophilic yeasts possess antineoplastic activity. Their action is observed in solid tumors -bladder cancer. Along with their cytotoxic effects yeasts possess a very good safety profile and can be part of future antitumor therapy.

Design and synthesis of novel 20(S)-α-aminophosphonate derivatives of camptothecin as potent antitumor agents

29 novel 20(S)-aminophosphonate derivatives of camptothecin were synthesized via a FeCl3 - catalyzed one-pot reaction. All of these compounds displayed similar or superior cytotoxic activity in comparison with that of Irinotecan against Hep3B, MCF-7, A-549, MDA-MB-231, KB, and multidrug-resistant (MDR) KB-vin cell lines. Out of them, compound B07 exhibited significant cytotoxicity and 10-fold improvement in activity compared to Irinotecan. Mechanistically, B07 not only induced cell apoptosis and cell cycle arrest in Hep3B and MCF-7 cells, but also inhibited Topoisomerase I activity in the cell and cell-free system in a manner similar to that of Irinotecan. In both xenograft and primary HCC mouse models, B07 showed significant anti-tumor activity and was more potent than Irinotecan. Additionally, the acute toxicity assay showed that B07 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the FVB/N mice. Therefore, these findings indicate that compound B07 could be a potential Topoisomerase I poison drug candidate for further clinical trial.

Synthesis via the Mannich Reaction and Biological Activity of Novel Fluorinated Camptothecin Derivatives

Synthesis via the Mannich Reaction and Biological Activity of Novel Fluorinated Camptothecin Derivatives