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High Yield Conversion of Doxorubicin to 2-Pyrrolinodoxorubicin

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High Yield Conversion of Doxorubicin to 2-Pyrrolinodoxorubicin Proc. Natl. Acad. Sci. USA Vol. 93, pp. 2464-2469, March 1996 Medical Sciences High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: Structure-activity relationship of daunosamine-modified derivatives of doxorubicin (cytotoxic agents/antineoplastic drugs/design and synthesis/steric factors/alkylating agents) ATrILA NAGY*t, PATRICIA ARMATIS*, AND ANDREW V. SCHALLY*t *Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, and tDepartment of Medicine, Tulane University School of Medicine, New Orleans, LA 70146 Contributed by Andrew V. Schally, December 4, 1995 ABSTRACT A convenient, high yield conversion of doxo- 8). This derivative was isolated as a highly potent by-product rubicin to 3'-deamino-3'-(2"-pyrroline-1"-yl)doxorubicin is that formed during the reductive alkylation of the described. This daunosamine-modified analog of doxorubicin daunosamine nitrogen of DOX. MRA-CN was 100-500 is 500-1000 times more active in vitro than doxorubicin. The times more active than DOX in vitro. In fact, MRA-CN conversion is effected by using a 30-fold excess of 4-iodobu- proved to be 1500 times more potent on cell lines resistant tyraldehyde in anhydrous dimethylformamide. The yield is to DOX (9-11). It was revealed that the extremely high higher than 85%. A homolog of this compound, 3'-deamino- activity of this compound, even against DOX-resistant tumor 3'-(1l,3"-tetrahydropyridine-1"-yl)doxorubicin, was also syn- cell lines, is a result of its ability to form an aminal adduct thesized by using 5-iodovaleraldehyde. In this homolog, the with an amino group of a guanine base in close vicinity to its daunosamine nitrogen is incorporated into a six- instead of a binding site (12, 13). Based on this knowledge, a class of five-membered ring. This analog was 30-50 times less active intensely potent analogs was developed, best represented by than its counterpart with a five-membered ring. A similar N-(5,5-diacetoxypent-1-yl)doxorubicin (14, 15). This analog structure-activity relationship was found when 3'-deamino- is a water soluble, latent aldehyde derivative, activated in 3'-(3"-pyrrolidone-1"-yl)doxorubicin (containing a five- tissues by carboxylate esterase enzymes to become 150 times membered ring) and 3'-deamino-3'-(3"-piperidone-1"- more active than DOX. Other semisynthetic derivatives, like yl)doxorubicin (with a six-membered ring) were tested in vitro, and the former being 5 times more potent than the latter. To morpholinodoxorubicin (7) 2-methoxymorpholinodoxo- further elucidate structure-activity relationships, 3'- rubicin, become 50-80 times more active in vivo after deamino-3'-(pyrrolidine-1"-yl)doxorubicin, 3'-deamino-3'- activation by liver enzymes (16, 17). (isoindoline-2"-yl)doxorubicin, 3'-deamino-3'-(2"-methyl-2"- These highly potent analogs of DOX either have a latent pyrroline-l"-yl)doxorubicin, and 3'-deamino-3'-(3Y-pyrroline- aldehyde derivative attached to the nitrogen atom in the 1"-yl)doxorubicin were also synthesized and tested. All the daunosamine moiety through an open chain polymethylene analogs were prepared by using reactive halogen compounds bridge or the nitrogen atom becomes a part of a morpholine for incorporating the daunosamine nitrogen of doxorubicin ring. Gao et al. (18) presented a high resolution x-ray diffrac- into a five- or six-membered ring. These highly active anti- tion picture of a covalently linked adduct between a synthetic neoplastic agents can be used for incorporation into targeted DNA segment and a daunorubicin derivative. This adduct cytotoxic analogs of luteinizing hormone-releasing hormone forms readily when traces of formaldehyde are present in the intended for cancer therapy. crystallization solvent. The daunosamine nitrogen atom of the anthracycline derivative was shown to be linked covalently Daunorubicin and doxorubicin (DOX) (Fig. 1) are members of through a methylene bridge to the amino group of an amino- the family of the anthracycline antibiotics (1, 2) that were adenine moiety of the DNA segment in close vicinity. introduced into cancer therapy about 3 decades ago. As a result Based on these findings, we decided to investigate further of a small structural difference, DOX is a much more potent the structural requirements for the design of intensely potent anticancer agent than daunorubicin. Since its introduction into doxorubicin analogs. Our efforts led to the high yield (85%) human cancer therapy, DOX is still the most widely used conversion of DOX to 2-pyrrolinodoxorubicin by the use of a chemotherapeutic drug, with the broadest spectrum of anti- 30-fold excess of 4-iodobutyraldehyde. 2-Pyrrolinodoxorubicin tumor effect (3). is a stable, water soluble analog, which is 500-1000 times more The antiproliferative activity of DOX is due mainly to its active than its parent compound in vitro. ability to intercalate into DNA and break the strands of double helix by inhibiting topoisomerase 11 (4). Despite its wide acceptance in the chemotherapy of various cancers, prolonged MATERIALS AND METHODS use of DOX is severely limited by cardiotoxicity (5). Another Materials. DOX HCl salt, 1,4-diiodobutane, a,a'-dichloro- limitation of DOX is multidrug resistance (6). ortho-xylene, cis-1,4-dichloro-2-butene, 3-bromopropionyl Thousands of anthracycline derivatives were synthesized chloride, and 4-bromobutyryl chloride were purchased from to overcome these limitations and in search for even more Aldrich. Silica gel (Merck grade 9385; 230-400 mesh; pore active analogs (3). One of the most significant milestones in size, 60 A) was also from Aldrich. TLC aluminum sheets the semisynthetic development of more potent, non-cross- precoated with silicagel 60 F254 by Merck Art no. 5554 were resistant analogs of DOX with lower cardiotoxicity was the obtained from Curtin Matheson Scientific (Houston). 2-(3- finding of 3-cyanomorpholinodoxorubicin (MRA-CN) (7, Chloropropyl)-1,3-dioxolane, 2-(3-chloropropyl)-2-methyl- The publication costs of this article were defrayed in part by page charge Abbreviations: DIPEA, N,N-diisopropylethylamine; DMF, N,N- payment. This article must therefore be hereby marked "advertisement" in dimethylformamide; DOX, doxorubicin; MRA-CN, 3-cyanomorpho- accordance with 18 U.S.C. §1734 solely to indicate this fact. linodoxorubicin; TFA, trifluoroacetic acid. 2464 Downloaded by guest on October 1, 2021 Medical Sciences: Nagy et al. Proc. Natl. Acad. Sci. USA 93 (1996) 2465 O OH oil was dissolved in 3 ml of 0.1% TFA in H20 and extracted with ether to remove excess 1,4-diiodobutane. Purification 14 by HPLC resulted in 41.6 mg of 98% pure DOX derivative 12 CH2 -R (yield, 68%). Preparation of 3'-deamino-3'-(isoindoline-2"-yl)doxorubicin TFA salt (AN-184). DOX HCl salt (50 mg; 86 ,umol) was CH3/ dissolved in 1 ml of DMF and 226 mg (1.3 mmol; 15-fold excess) of a,a'-dichloro-ortho-xylene was added followed by 45 H3C ,tl (260 ,tmol; 3-fold excess) of DIPEA and a catalytic amount of Nal. After 16 hr, the reaction was complete and the desired end product was isolated as given above (yield, 55%). NH2 OH Preparation of 3'-deamino-3'- (3"-pyrroline-1"-yl)doxorubicin TFA salt (AN-185). DOX HCl salt (50 mg; 86 ,umol) was FIG. 1. Structures of daunorubicin (R = H) and DOX (R = OH). dissolved in 1 ml of DMF and 136.8 gl (1.3 mmol; 15-fold The daunosamine amino sugar moiety is indicated by an arrow. excess) of cis-1,4-dichloro-2-butene was added, followed by 45 ,ul (260 3-fold excess) of DIPEA. After 16 hr, the 1,3-dioxolane, and 2-(4-chlorobutyl)-1,3-dioxolane were ,tmol; reaction mixture was worked up as described above, yielding bought from Fluka. 22.6 mg of 98% pure end product (yield, 37%). Synthesis. Preparation of 1-chloro-4-bromo-2-butanone Preparation of 3'-deamino-3'-(3"-pyrrolidone-1"-yl)doxoru- and 1-chloro-5-bromo-2-butanone. 3-Bromopropionyl chlo- bicin TFA salt (AN-191) and 3'-deamino-3'-(3"-piperidone- ride (100.8 1lI; 1 mmol) was reacted with excess diazometh- 1"-yl)doxorubicin TFA salt (AN-195). DOX HCl salt (50 mg; ane in ether for 1 hr. The ethereal solution was developed in 86 ,umol) was dissolved in 1 ml of DMF and 241 mg (1.3 CHCl3/MeOH (95:5, vol/vol) on TLC. After chromatogra- mmol; 15-fold excess) of 1-chloro-4-bromo-2-butanone was phy, 2,4-dinitrophenylhydrazine reagent (19) was sprayed on added followed by 45 ,ul (260 ,umol; 3-fold excess) of DIPEA. the TLC sheet. The diazomethylketone derivative thus After 16 hr, the reaction mixture was purified as cited above, formed showed a yellow spot with Rf = 0.3. The ethereal yielding 20.6 mg of 98% pure end product (yield, 33%). solution was then reacted with anhydrous HCl in ether, 3'-Deamino-3'-(3"-piperidone-1"-yl)doxorubicin was pre- converting the diazomethylketone to the desired end prod- pared similarly by using 1-chloro-5-bromo-2-pentanone uct, 1-chloro-4-bromo-2-butanone. This compound showed a (yield, 28%). yellow spot, characteristic of oxo compounds, with Rf = 0.8 Preparation of 3'-deamino-3'-(2"-pyrroline-1"-yl)doxorubicin in the same solvent system and with the spot test reagent TFA salt (AN-201), 3'-deamino-3'-(1",3"-tetrahydropyridine-1"- described above. After evaporation of the solvent, the crude yl)doxorubicin TFA salt (AN-205), and 3'-deamino-3'-(2"- product was applied on a column (2.5 x 15 cm) packed with methyl-2"-pyrroline-1"-yl)doxorubicin (AN-204). DOX HCl salt 15 g of silica gel. The liquid, mobile phase was CHCl3. (50 mg; 86 ,tmol) was dissolved in 1 ml of DMF and 515 mg Fractions containing the desired end product (characterized (2.6 mmol) of 30-fold excess 4-iodobutyraldehyde was added by the spot test) were combined and evaporated to dryness followed by 45 gl (260 jLmol; 3-fold excess) of DIPEA.
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