Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labelled chelating peptide conjugates as a theranostic tool for cancer

• Published in: Beilstein journal of organic chemistry Vol. 14; no. 1; pp. 2665 - 2679
• Main Authors: Sengupta, Sagnik, Krishnan, Mena Asha, Dudhe, Premansh, Reddy, Ramesh B, Giri, Bishnubasu, Chattopadhyay, Sudeshna, Chelvam, Venkatesh
• Format: Journal Article
• Language: English
• Published: Germany Beilstein-Institut zur Föerderung der Chemischen Wissenschaften 18.10.2018; Beilstein-Institut
• Subjects: Amino acids; Arthritis; Biomarkers; chelating linker; Chemistry; confocal studies; continuous synthetic process; Discipline; fluorescent tag; Fmoc-Lys-(Tfa)-OH; Full Research Paper; Inflammatory diseases; Lasers; Ligands; Medical imaging; Microscopy; NMR; Nuclear magnetic resonance; Ovarian cancer; Peptides; Prostate; prostate cancer and ovarian cancer; Resins; solid-phase peptide synthesis; Tomography; Vitamin B; India; Fmoc-Lys-(Tfa)-OH; confocal studies; solid-phase peptide synthesis; fluorescent tag; prostate cancer and ovarian cancer; chelating linker; continuous synthetic process
• ISSN: 1860-5397; 2195-951X; 1860-5397
• DOI: 10.3762/bjoc.14.244

In this article, we have successfully designed and demonstrated a novel continuous process for assembling targeting ligands, peptidic spacers, fluorescent tags and a chelating core for the attachment of cytotoxic molecules, radiotracers, nanomaterials in a standard Fmoc solid-phase peptide synthesis in high yield and purity. The differentially protected Fmoc-Lys-(Tfa)-OH plays a vital role in attaching fluorescent tags while growing the peptide chain in an uninterrupted manner. The methodology is versatile for solid-phase resins that are sensitive to mild and strong acidic conditions when acid-sensitive side chain amino protecting groups such as Trt (chlorotrityl), Mtt (4-methyltrityl), Mmt (4-methoxytrityl) are employed to synthesise the ligand targeted fluorescent tagged bioconjugates. Using this methodology, DUPA rhodamine B conjugate (DUPA = 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid), targeting prostate specific membrane antigen (PSMA) expressed on prostate, breast, bladder and brain cancers and pteroate rhodamine B, targeting folate receptor positive cancers such as ovarian, lung, endometrium as well as inflammatory diseases have been synthesized. In vitro studies using LNCaP (PSMA +ve), PC-3 (PSMA -ve, FR -ve) and CHO-β (FR +ve) cell lines and their respective competition experiments demonstrate the specificity of the newly synthesized bioconstructs for future application in fluorescent guided intra-operative imaging.