Photochemical Reactions of Carbohydrates

Publisher Summary Doxorubicin is one member of the anthracycline group of antibiotics and is produced by a variant of the organism that produces daunorubicin (2) (trivial name, daunomycin), the latter drug being preferred in the treatment of acute leukemia, as it is equiactive and lower in cost. Despite its good antitumor activity, doxorubicin is far from an ideal drug as it has both pharmaceutical and toxicological limitations. This chapter focuses on synthetic routes to doxorubicin and other anthracyclines. It discusses the biochemical effects of doxorubicin and analogues of doxorubicin. Most of the work on synthetic routes to anthracyclines has concentrated on doxorubicin (1) and the related compounds, daunorubicin (2) and carminomycin (12). The stimulus has been the low yield of doxorubicin (1) from the fermentation process and the challenge of synthesis of a compound of such complexity. Only recently has attention really widened to synthesis of other natural anthracyclines. The major problem in design of a route is to obtain regiochemical and stereochemical control. New potentially clinically useful analogues have arrived by screening of natural products or by chemically based intuitive semisynthesis and synthesis, rather than by truly rational design.

Recent studies on doxorubicin and its analogues.

This invention provides an aqueous/t-butanol solvent-system, facile reconstitute, submicron-reconstitute preliposome-lyophilate and method of its preparation and use. In one embodiment, a modified method for the preparation of a submicron and stable liposome formulation of the non cross-resistant anthracycline Annamycin is described. The optimal lipid composition was DMPC:DMPG at a 7:3 molar ratio and the optimal lipid:drug weight ratio 50:1. The selected formulation is a preliposome lyophilized powder that contains the phospholipids, Annamycin, and 1.7 mg Tween 20 per mg of Annamycin. The liposome suspension is obtained on the day of use by adding normal saline at 37 °C (1 ml per mg Annamycin) and hand-shaking for one minute. The presence of Tween 20 is essential in shortening the reconstitution step (from > 2 hours to 1 minute), avoiding the early formation of free drug crystals, and reducing the median particle size (from 1.5 νm to 0.15-0.20 νm) without destruction of the liposome vesicles. The chemical stability of the preliposome powder at room temperature was > 3 months and the chemical and physical stability of the liposome suspension at room temperature > 24 hours. The in vitro cytotoxicity of the formulation was equivalent to that prepared by the standard evaporation method. The results of the study indicate that small amounts of surfactant may be used to enhance the reconstitution step and reduce the liposome size of lyophilized liposome formulations of lipophilic drugs.

Submicron liposome suspensions obtained from preliposome lyophilizates

Synthesis and antitumor activity of 7-O-(3,4-di-O-acetyl-2,6-dideoxy-α-l-lyxo-hexopyranosyl)adriamycinone

Compounds of the formula (I), acid addition salts thereof, and pharmaceutical preparations containing the same are disclosed ##STR1## wherein R1 is hydroxy; one of X and X' is hydrogen and the other is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine; one of Y and Y' is hydrogen and the other is selected from the group consisting of hydrogen, hydroxy and --OCOR; one of Z and Z' is hydrogen and the other is hydrogen, hydroxy or --OCOR; and R is a lower alkyl group.

4-Demethoxy-3'-desamino-2'-halo-anthracycline and pharmaceutical composition containing same

A series of compounds showing high antileukemic activity against P388 murine leukemia and increased aqueous solubility due to substitution of -OH for the known -NH2 at the 3' position of the hexopyranose sugar, i.e., daunosamine. These compounds are coupled products of aglycon selected from daunomycinone, desmethoxy daunomycinone, adriamycinone and carminomycinone. These compounds are coupled at the 0-7 position of the aglycon with an alpha -L-lyxo hexopyranose sugar, which sugar isomer particularly sustains or potentiates the biological activity of the coupled compound as well as ameliorates the dose related cardiotoxicity of the parent and known compounds set out below:

7-O-(2,6-Dideoxy- alpha -L-lyxo-hexopyranosyl)-daunomycinone, desmethoxy daunomycinone, adriamycinone, and carminomycinone

A series of compounds showing high antileukemic activity against P388 murine leukemia and increased aqueous solubility due to substitution of --OH for the known --NH2 at the 3' position of the hexopyranose sugar, i.e., daunosamine. These compounds are coupled products of aglycon selected from daunomycinone, desmethoxy daunomycinone, adriamycinone and carminomycinone. These compounds are coupled at the 0-7 position of the aglycon with an α-L-lyxo hexopyranose sugar, which sugar isomer particularly sustains or potentiates the biological activity of the coupled compound as well as ameliorates the dose related cardiotoxicity of the parent and known compounds set out below: ##STR1##

7-O-(2,6-Dideoxy-α-L-lyxo-hexopyranosyl)-daunomycinone, desmethoxy daunomycinone, adriamycinone, and carminomycinone

Glycosidation of 2, 3, 6-trideoxy-3-trifluoroacclamido-4-O-tritluoroacetyl-α-D-arabino-hexopyranosyl chloride (19) (or the corresponding 4-p-nitrobenzoate, 20) with daunomycinone under KOENIGS-KNORR conditions afforded, after separation of the anomers and removal of the protecting groups, the individual target glycosides 8 (α anomer; major product) and 9 (β; minor) in acceptable yields. In contrast, the title diamino sugar, suitably protected with N-trifluoroacetyl and O-acetyl (or O-p-nitrobenzoyl) groups, underwent stereospecific coupling to the anthracycline aglycon by the glycal procedure to give, after deprotection, the α glycoside 12. All three analogs were assayed in vivo against P388 lymphocytic leukemia. They showed little (T/C 125 for 8; T/C 115 for 9) or no (compound 12) activity, but were essentially devoid of toxicity at the dose-levels tested.

New daunorubicin analogs. 3-Amino-2,3,6-trideoxy-alpha- and beta-D-arabino- and 3,6-diamino-2,3,6-trideoxy- alpha-D-ribo-hexopyranosides of daunomycinone.

A series of compounds showing high antileukemic activity against P388 murine leukemia and increased aqueous solubility due to substitution of -0H for the known -NH2 at the 3' position of the hexopyranose sugar, i.e., daunosamine. These compounds are coupled products of aglycon selected from desmthoxy daunomycinone, adriamycinone, and carminomycinone. These compounds are coupled at the 0-7 position of the aglycon with an (Alpha)-L-lyxo hexopyranose sugar, which sugar isomer particularly sustains or potentiates the biological activity of the coupled compound as well as ameliorates the dose related cardiotoxicity of the parent and known compounds set out below:

Beat Winter

Papers

7-O-(2,6-Dideoxy- alpha -L-lyxo-hexopyranosyl)-daunomycinone, desmethoxy daunomycinone, adriamycinone, and carminomycinone

7-O-(2,6-Dideoxy-α-L-lyxo-hexopyranosyl)-daunomycinone, desmethoxy daunomycinone, adriamycinone, and carminomycinone

New daunorubicin analogs. 3-Amino-2,3,6-trideoxy-alpha- and beta-D-arabino- and 3,6-diamino-2,3,6-trideoxy- alpha-D-ribo-hexopyranosides of daunomycinone.

7-0-(2,6-DIDEOXY-.alpha.-L-LYXO-HEXOPYRANOSYL)- DESMETHOXY DAUNOMYCINONE, ADRIAMYCINONE, AND CARMINOMYCINONE

Synthesis of two 3-amino-2,3-dideoxyhexuronic acid derivatives☆