The core heterocycle in surfen, 4,6-diamino-2-methylquinoline (14), was synthesized as previously reported and was used in the synthesis of surfen analogs 2–4 and 7–13 (Schemes 1 and 2).27 ,28 4-Aminoacetanilide (15) was condensed with ethyl acetoacetate to give ethyl-β-(p-acetamidophenylamino) crotonate (16). This ethyl ester intermediate then underwent thermal cyclization in Dowtherm A to yield 6-acetamide-4-hydroxy-2-methylquinoline (17). The hydroxyquinoline intermediate was then methylated with dimethyl sulfate to yield the methoxy derivative (18). This compound then underwent a two-step reaction to yield 4,6-diamino-2-methylquinoline (14) through a 6-acetamido-4-aminoquinaldine intermediate (19). This building block was used in the synthesis of specific surfen analogs (4–13) (Schemes 2 and 3).
1,3-Bis(2-methylquinolin-6-yl)urea (deaminated surfen) (6) was synthesized by reacting triphosgene with the commercially available 6-amino-2-methylquinoline in acetic acid. Furthermore, compounds 7–13 were synthesized using their respective diacid chlorides in acetic acid at room temperature. These compounds (7–13) were named according to the diacid chloride used in their synthesis. This procedure was adapted from a previous report.23 (link) 4-Amino-2-methyl-6-quinolyl-urea (hemisurfen) (2) was prepared using potassium cyanate, 10% acetic acid, and water followed by recrystallization from water. Finally, 6-acetamido-4-aminoquinaldine (acetyl-hemisurfen) (3) was synthesized by reacting 4,6-diaminoquinaldine with acetic chloride in acetic acid, and N,N′-bis-(4-amino-2-methyl-6-quinolyl)-thiourea (thio surfen) (4) was synthesized using thiophosgene in DMF. Hemisurfen and acetyl-hemisurfen were recrystallized from water, while all other final products were recrystallized from hot DMF by the addition of diethyl ether. To synthesize the methoxy analog 1,3-bis(4-methoxy-2-methyl-quinolin-6-yl)urea (methoxy surfen) (5), 6-acetamido-4-methoxyquinaldine (18) was deprotected with 37% HCl in H2O to form 6-amino-4-methoxyquinaldine (20). This compound was then reacted with triphosgene to yield 5 (Scheme 3).
Surfen (bis-2-methyl-4-amino-quinolyl-6-carbamide) was previously obtained from the National Cancer Institute as a hydrochloride salt (NCI 12155). All compounds were therefore converted to their hydrochloride salts for use in biological assays. The hydrochloride products were precipitated from an appropriate solvent using 4 M HCl in 1,4-dioxane (Scheme S1†). The products were analyzed using 1H NMR, 13C NMR, and ESI-MS. An X-ray crystal structure of one of the analogs (13) confirmed that these molecules are doubly protonated on their aminoquinoline ring systems (Fig. 3d). Furthermore, the X-ray structures of 1 and 13 displayed syn orientations in regards to their quinoline ring systems (Fig. 3a and d), while the crystal structures of oxalyl and adipoyl surfen displayed anti orientations (Fig. 3b and c). These structures suggest that surfen analogs within this collection could present diverse molecular configurations that could affect their interactions with the anionic subunits of HS.