Mono and bis(bioreductive) alkylating agents: synthesis and antitumor activities in a B16 melanoma model

Abstract

Several potentially bis(alkylating) bis(quinones) (3-5) and 1,4- and 1,3-bis(alkylating) monoquinones (6-13) belonging to general structure 2,2'-ethylenebis[5-[(leaving group)methyl]-1,4-benzoquinone] (3-5) and 2,5- and 2,6-bis[(leaving group)methyl]-1,4-benzoquinone water-soluble and -insoluble classes were prepared by oxidative demethylation of the corresponding tetramethoxydiphenylethanes (17-19) and dimethoxybenzenes (24, 27, 36-39), respectively. Methods employed for the preparation of tetramethoxydiphenylethane intermediates involved (1) arylmethyl bromide coupling and (2) catalytic hydrogenation of stilbene intermediates derived via Wittig reaction of (arylmethyl)phosphonium salts with aryl aldehydes. However, in biological investigations using a subcutaneous B16 (hypoxic) melanoma tumor in BDF1 hybrid mice with cyclophosphamide as positive control the most interesting series of structurally related analogues were the potentially monoalkylating monoquinones of the 2-[(leaving group)methyl]-1,4-benzoquinone type (i.e., 14 and 15) having water-insoluble (acetoxy) and water-solubilizing (succinate) groups. Serial measurements of tumor size, and evaluation of increased life span, in response to drug treatment also revealed potentially 1,4-bis(alkylating) (bromomethyl)-1,4-quinone 7 and 1,3-bis(alkylating) (hydroxymethyl)-1,4-quinone 10 to have variable activity, but none of the potentially bis(alkylating) bis(quinones) showed antitumor properties in this model.

Substituents Have a Large Effect on Photochemical Generation of Benzyl Cations and DNA Cross‐Linking

“…1,3‐Bis(bromomethyl)‐2,5‐dimethoxybenzene (1 a) : To a solution of 7 (1.66 g, 10 mmol) in benzene (40 mL), N ‐bromosuccinimide (3.56 g, 20 mmol) and azobisisobutyronitrile (164.21 mg, 1 mmol) were added and the reaction mixture was heated to reflux for 3 h. Solvent was removed and the residue was purified by column chromatography (hexane/DCM=5:1, R f =0.24) to afford 1 a as a white solid (1.70 g, 5.28 mmol); m.p. 92–93 °C; 1 H NMR (300 MHz, CDCl 3 ): δ =6.92 (s, 2 H), 4.55 (s, 4 H), 3.99 (s, 3 H), 3.82 ppm (s, 3 H) (the NMR spectra were in agreement with those reported) …”

“…Methyl iodide (8.22 g, 57.88 mmol) was added dropwise into the reaction mixture, which was allowed to warm to RT,s tirred at RT overnight, and then extracted with ethyl acetate (3 40 mL). [25] 1,1'-(2,5-Dimethoxy-1,3-phenylene)bis (N,N,N- 4-Methoxy-2,6-dimethyl-1,1'-biphenyl (9):T o8 (2.14 g, 10 mmol), phenylboronic acid (2.2 g, 18 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.15 g, 2mmol) in at wo-neck round-bottom flask (100 mL), was added THF (60 mL) under N 2 .As olution of K 2 CO 3 (6.9 g, 50 mmol) in water (20 mL) was then added by using as yringe. 1 HNMR (300 MHz, CDCl 3 ): d = 6.60 (s, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 2.31 pm (s, 6H) (the NMR spectra were in agreement with those reported).…”

A colorimetric chiral sensor based on chiral crown ether for the recognition of the two enantiomers of primary amino alcohols and amines

“…As a first step, ( R )‐3,3′‐diphenyl‐1,1′‐binaphthyl‐2,2′‐diol, which was prepared from ( R )‐1,1′‐binaphthyl‐2,2′‐diol via the known procedure,32 was treated with 2‐(2‐iodoethoxy)ethanol in the presence of potassium carbonate in acetonitrile to afford compound 2 . Compound 2 was deprotonated by treating with NaH in THF and then treated with 1,3‐bis(bromomethyl)‐2,5‐dimethoxybenzene, which was prepared via the procedure reported previously,33 to afford crown ether type compound 3 . The 1,4‐dimethoxyphenyl group of compound 3 was oxidized to the 1,4‐benzoquinone group of compound 4 by treating with ceric ammonium nitrate in the mixed solvent of acetonitrile and water.…”

Synthesis of Chiral Helic[1]triptycene[3]arenes and Their Enantioselective Recognition towards Chiral Guests Containing Aminoindan Groups

“…By the reaction of RR-1, 1,4-dimethoxybenzene 2 and 1,4-dihydroxymethyl-2,5-dimethoxybenzene 3 [25] with a catalytic amount of FeCl3 in dichloroethane, we conveniently obtained P-H with 42% yield. Similarly, starting from SS-1 and 2 and 3, we obtained M-H with 40% yield.…”