Synthesis of the first spacer containing prodrug of a duocarmycin analogue and determination of its biological activity

Abstract

The synthesis of the first spacer containing, duocarmycin analogue prodrug was realised, its biological properties evaluated and compared to its counterpart prodrug without a spacer unit. The synthesis comprises the manufacture of the new acetylated derivatives and of two double spacer systems, their activation and coupling to the pharmacophoric seco-drug (+)-. Unprecedented biological results were found as the new prodrug showed a fairly low QIC(50) value of 20, but on the other hand a high stability and very low DNA alkylation efficiency. These findings indicate a changed cytostatic mode of action induced by the self-immolative spacer moiety which was employed.

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

“…Thec yclization strategy has been applied in prodrugs, [4,[18][19][20][21][22][23][24][25][130][131][132][133][134] sensors, [34-36, 38, 41] and drug delivery sys- tems. [26-28, 30, 32, 88] Disassembly of self-immolative spacers based on intramolecular 5-exo-trig or 6-exo-trig cyclization yields cyclic esters,u reas,c arbamates,o rt hiocarbonates [59,63] (Figure 3a-c).…”

“…Since their introduction in 1981, [11][12][13][14][15][16][17] self-immolative spacers found applications in prodrugs, [4,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] sensors for chemicals or enzymes, [33][34][35][36][37][38][39][40][41] and for drug delivery. [26-28, 30-32, 42-46] Self-immolative spacers are also increasingly used in materials science, [47][48][49][50][51] where their unique feature of kinetically programmable auto-destruction provides unprecedented opportunities for sustainable matter management( i.e.…”

Synthesis of Imidazole and Theophylline Derivatives Incorporating Pyrimidine‐Fused Heterocycles Using Magnetic Nanoparticles‐Supported Tungstic Acid (MNP‐TA) Catalyst

“…Compounds with two or more heterocyclic moieties are important in medicinal chemistry . In most cases, the heterocyclic moieties connected to each other via a spacer which the type and length of spacer have significant effects on biological activity of these compounds . Imidazole and benzimidazole heterocycles have been found in the structure of many biological active compounds because of their widespread biological activities .…”

Ein niedermolekulares Ligand‐Wirkstoff‐Konjugat zur Behandlung von Carboanhydrase IX exprimierenden Tumoren

“…Beide Giftstoffe waren zuvor in der Entwicklung von Antikçrper-Wirkstoff-Konjugaten eingesetzt worden. [11,31,32] Den Konjugaten 7 b, 8 b und 9 b fehlte AAZ als Transportligand; sie wurden als Negativkontrollen eingesetzt. Reduktionsmittel (z.…”

“…[11] Der Transportligand wurde Carbamatrest so ausgelegt, dass er spontan zerfallen und den aktiven Giftstoff freisetzen würde. [11,31,32] Den Konjugaten 7 b, 8 b und 9 b fehlte AAZ als Transportligand; sie wurden als Negativkontrollen eingesetzt.…”