title: Synthetic lactulose amines: novel class of anticancer agents that induce tumor-cell apoptosis and inhibit galectin-mediated homotypic cell aggregation and endothelial cell morphogenesis.
abstract: Galectins, a family of structurally related carbohydrate-binding proteins, contribute to different events associated with cancer biology, including apoptosis, homotypic cell aggregation, angiogenesis and tumor-immune escape. To interfere with galectin-carbohydrate interactions during tumor progression, a current challenge is the design of specific galectin inhibitors for therapeutic purposes. Here, we report the synthesis of three novel low molecular weight synthetic lactulose amines (SLA): (1) N-lactulose-octamethylenediamine (LDO), (2) N,N'-dilactulose-octamethylenediamine (D-LDO), and (3) N,N'-dilactulose-dodecamethylenediamine (D-LDD). These compounds showed a differential ability to inhibit binding of galectin-1 and/or galectin-3 to the highly glycosylated protein 90K in solid-phase assays. In addition, each compound demonstrated selective regulatory effects in different events linked to tumor progression including tumor-cell apoptosis, homotypic cell aggregation, and endothelial cell morphogenesis. Our results suggest that galectin inhibitors with subtle differences in their carbohydrate structures may be potentially used to specifically block different steps of tumor growth and metastasis.
authors.affiliation: Division of Immunogenetics, Hospital de Clínicas "José de San Martín," University of Buenos Aires, Buenos Aires, Argentina. gabyrabi@ciudad.com.ar
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.forename: Albana
authors.initials: A
authors.lastname: Cumashi
authors.forename: Germán A
authors.initials: GA
authors.lastname: Bianco
authors.forename: Domenico
authors.initials: D
authors.lastname: Ciavardelli
authors.forename: Ida
authors.initials: I
authors.lastname: Iurisci
authors.forename: Maurizia
authors.initials: M
authors.lastname: D'Egidio
authors.forename: Enza
authors.initials: E
authors.lastname: Piccolo
authors.forename: Nicola
authors.initials: N
authors.lastname: Tinari
authors.forename: Nikolay
authors.initials: N
authors.lastname: Nifantiev
authors.forename: Stefano
authors.initials: S
authors.lastname: Iacobelli
mesh_terms: D000588:Amines / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002449:Cell Aggregation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D037161:Galectins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006031:Glycosylation; D006801:Humans; D007792:Lactulose / Q000737:chemistry*; D015394:Molecular Structure
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D037161:Galectins; D007792:Lactulose