Camptothecin is a complex monoterpenoid indole alkaloid with remarkable antitumor activity. Given that two C-10 modified camptothecin derivatives, topotecan and irinotecan, have been approved as potent anticancer agents, there is a critical need for methods to access other aromatic ring-functionalized congeners (e.g., C-9, C-10, etc.). However, contemporary methods for chemical oxidation are generally harsh and low-yielding when applied to the camptothecin scaffold, thereby limiting the development of modified derivatives. Reported herein, we have identified four tailoring enzymes responsible for C-9 modifications of camptothecin from Nothapodytes tomentosa, via metabolomic and transcriptomic analysis. These consist of a cytochrome P450 (NtCPT9H) which catalyzes the regioselective oxidation of camptothecin to 9-hydroxycamptothecin, as well as two methyltransferases (NtOMT1/2, converting 9-hydroxycamptothecin to 9-methoxycamptothecin), and a uridine diphosphate-glycosyltransferase (NtUGT5, decorating 9-hydroxycamptothecin to 9-β-D-glucosyloxycamptothecin). Importantly, the critical residues that contribute to the specific catalytic activity of NtCPT9H have been elucidated through molecular docking and mutagenesis experiments. This work provides a genetic basis for producing camptothecin derivatives through metabolic engineering. This will hasten the discovery of novel C-9 modified camptothecin derivatives, with profound implications for pharmaceutical manufacture.
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http://dx.doi.org/10.1111/jipb.13649 | DOI Listing |
Bioorg Med Chem Lett
December 2024
Pinotbio, Inc Suwon, Gyeonggi-do 16506, South Korea.
FL118, a camptothecin derivative with dual mechanisms of action through topoisomerase I inhibition and proteasome-mediated degradation of anti-apoptotic proteins exhibits potent anti-tumor activity while remaining resistant to drug efflux transporters. This work describes the targeted delivery of FL118 to tumors via antibody-drug conjugates (ADCs) using the pH-sensitive CL2A linker. ADCs targeting Trop2, HER2, and EGFR exhibited potent in vitro cytotoxicity, with IC values as low as 0.
View Article and Find Full Text PDFACS Nano
December 2024
School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 511442, P. R. China.
Chemotherapy is the primary treatment option for pancreatic cancer, although nanocarrier-based drug delivery systems often struggle with multiple physiological barriers, limiting their therapeutic efficacy. Here, we developed a pH/reactive oxygen species (ROS) dual-sensitive self-adaptive nanocarrier (DAT) encapsulating camptothecin (CPT), an analog of the pancreatic chemotherapeutic drug irinotecan (CPT-11), to enhance chemotherapy outcomes in orthotopic pancreatic cancer by addressing multiple physiological barriers. The nanocarrier features a peripherally positively charged arginine (Arg) residue on DAT and is masked with an acid-labile 2,3-dimethylmaleic anhydride (DA) to improve circulation time.
View Article and Find Full Text PDFACS Omega
December 2024
Department of Biochemistry and Microbiology, North South University, Bashundhara, Dhaka 1229, Bangladesh.
Cancer is characterized by uncontrolled cell growth and spreading throughout the body. This study employed computational approaches to investigate 18 naturally derived anticancer piscidinol A derivatives (-) as potential therapeutics. By examining their interactions with 15 essential target proteins (HIF-1α, RanGAP, FOXM1, PARP2, HER2, ERα, NGF, FAS, GRP78, PRDX2, SCF complex, EGFR, Bcl-xL, ERG, and HSP70) and comparing them with established drugs such as camptothecin, docetaxel, etoposide, irinotecan, paclitaxel, and teniposide, compound emerged as noteworthy.
View Article and Find Full Text PDFPlant Physiol Biochem
December 2024
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610213, China. Electronic address:
Cytochrome P450 enzymes (CYPs), the members of the largest superfamily of enzymes in plant kingdom, catalyze a variety of functional group transformations involved in metabolite biosynthesis, end-product derivatization, and exogeneous molecule detoxification. Nevertheless, CYPs' functional characterization and practically industrial application have been largely encumbered by their critical dependency on the reducing equivalent for the catalytic cycling, driven by the tedious electron relay mediated by CYP reductase (CPR). Here, we report a photoinduced electron transfer system that initiates and sustains the CYP-catalyzed reaction cycling.
View Article and Find Full Text PDFBioorg Chem
December 2024
Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences, Central University of Punjab, Bathinda 151 401, India. Electronic address:
In this study, we herein report the design, synthesis, and anticancer assessment of a series of new 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines. The synthesis involved key intermediates such as the 2-aminoester derivative, which underwent a series of reactions to produce compounds 7a-7t. The optimized SAr reactions, utilizing microwave irradiation in DMF, led to high yields and efficient preparation of the desired compounds.
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