Charles R. West

Synthesis and antitumor activity of 1-β-D-arabinofuranosylcytosine conjugates of cortisol and cortisone

Abstract Superior antitumor activity of 1-β-D-arabinofuranosylcytosine (ara-C) conjugates of prednisolone and prednisone against L1210 leukemic mice, based on ara-C content, has encouraged us to synthesize 5′-(cortisone-21-phosphoryl)-1-β-D-arabinofuranosylcytosine (I) and 5′-(cortisone-21-phosphoryl)-1-β- d -arabinofuranosylcytosine (II) by condensation of N 4 ,2′,3′-triacetyl-1-β- d -arabinofuranosylcytosine 5′-monophosphate with cortisol and cortisone in the presence of N,N′-dicyclohexylcarbodiimide at room temperature followed by removing the acetyl groups in 2 N methanolic ammonia in 20% yield. The conjugates I and II inhibited the in vitro growth of L1210 by 50% (ED 50 ) at 0.25 μM and 0.07 μM, respectively, while ara-C showed ED 50 0.1 μM. However, the conjugates I and II exhibited 287% and 238% of T C at 50 mg/kg/day × 5 doses against L1210 leukemic mice, respectively, while ara-C at 25 mg and 50 mg/kg/day × 5 gave the respective 127% and 110% of T C .

1-β-D-arabinofuranosylcytosine conjugates of ether and thioether phospholipids : a new class of ara-C prodrug with improved antitumor activity

The 1-β-D-arabinofuranosylcytosine (ara-C) conjugates 1-O-alkyl (ether) and 1-S-alkyl (thioether) phospholipids, being analogues of ara-CDP-sn-1,2-O-dipalmitoylglycerol (1), showed significant antitumor activity against L1210 and P388 leukemiain vivo. The more active conjugates include the 1-O-alkyl analogues, ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (2) and ara-CDP-rac-1-O-octadecyl-2-O-palmitoylglycerol (3), and the corresponding 1-S-alkyl analogues, ara-CDP-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (4) and ara-CDP-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (5, Cytoros). The conjugates were formulated by sonication, in which the conjugates existed as discs (size 0.01–0.04 μ).. Among the conjugates of the three different phospholipids, the 1-S-alkyl analogues 4 and 5 displayed the strongest antitumor activity against L1210 leukemia in mice, followed by the 1-O-alkyl (2 and 3) and the 1-O-acyl (1) analogues. The 1-S-alkyl analogue 5 was considerably more effective than the 1-O-acyl analogue 1 against myelomonocytic WEHI-3B leukemia in mice. Conjugate 5 (Cytoros) showed a significant therapeutic activity in mice with colon 26 carcinoma, M5076 sarcoma, and C-1300 neuroblastoma. Furthermore, this agent inhibited liver metastases of M5076 sarcoma. Conjugates 3 and 5 also inhibited the metastasis of 3-Lewis lung carcinoma to the lungs of mice. Cytoros (5) and its analogues, with other ether and thioether phospholipids, appear to offer increased therapeutic benefit to mice with tumors.

Antineoplastic activity of conjugates of lipids and 1-β-d-arabinofuranosylcytosine

Five different lipid conjugates of 1-β-D-arabinofuranosylcytosine (ARA-C) were tested in comparison with ARA-C, the ether lipid ET-18-OCH3 (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) and their equimolar mixtures. The compounds were tested in vitro for cytotoxicity in the trypan blue dye exclusion test with cells from six different leukemias, one glioblastoma and two bronchogenic carcinomas of human origin. The compounds were given in vivo to assess their therapeutic activity against 3-Lewis lung carcinoma (3-LL) of syngeneic C57Bl6 mice. Although some of the conjugates have shown cytotoxic activity in vitro against the cell samples tested, they have not revealed higher cytotoxicity than ET-18-OCH3, ARA-C or their equimolar mixtures. In these experiments, ARA-CDP-D,L-MBA was the conjugate with the highest cytotoxicity. Some of the conjugates significantly inhibited tumor growth and also increased survival of C57Bl6 mice with intraperitoneally (ip) implanted 3-LL. In these experiments, ARA-CDP-D,L-PTBA, ARA-CDP-D,L-PBA, ARA-CDP-L-dipalmitin and ARA-CDP-D,L-PCA were more active than either the parent compounds ARA-C and ET-18-OCH3 alone or their equimolar mixtures. Furthermore, when the conjugates were injected as adjuvant chemotherapy shortly after the surgical removal of the primary 3-LL, they inhibited the metastasis of 3-LL to the lungs of the animals, demonstrated by an increase of the survival time and the number of surviving animals. The mode of action of these new antineoplastic compounds still is speculative.

Management of intractable back pain from caudal ependymoma with spinal methylprednisolone, bupivacaine and morphine

Abstract We report the successful management of severe, intractable low back pain in a 21-year-old female with an ependymoma of the cauda equina using intermittent intrathecal methylprednisolone (20 mg), bupivacaine (2.5 mg) and morphine (1 mg) injections over a 2-year period.

1-β-d-Arabinofuranosylcytosine conjugates of corticosteroids as potential antitumor agents

Abstract The antitumor activity and toxicity of two new 1-β-d-arabinofuranosylcytosine (ara-C) conjugates of cortisol and corticosterone linked through a phosphodiester bond between the 5′ and 21 positions of the respective moieties (cortisol- and corticosterone- p -ara-C) were investigated in L1210 lymphoid leukemia cells in mice. They are highly active against both i.p.- and i.c.-implanted ara-C-sensitive lymphoid leukemia in mice, exceeding the activity produced by the parent drug, ara-C. For example, corticosterone- p -ara-C exhibited the respective ILS values of 306% at 50 mg/kg/day × 9 and 294% at 75 mg/kg/day × 9 on survivals of i.p.- and i.c.-inoculated L1210 leukemic mice. The effectiveness of the conjugates seems to depend on schedules of the treatments. The 9-day continuous treatments showed a better therapeutic effectiveness than those with either a 5-day, a single or a widely spaced (q 4 d., 1, 5, 9) treatment. However, they were found to be marginally effective against i.p.-implanted ara-C-resistant L1210 leukemia in mice. They were also inhibitory against proliferation of human leukemia-lymphoid cells in culture. Their superior antitumor activity and resistance to cytidine deaminase suggests that they serve as a prodrug form of ara-C or ara-CMP.

Synthesis and antitumor activity of 1-β-D-arabinofuranosylcytosine conjugates of optical isomers of ether and thioether lipids

Four 1-β-D-arabinofuranosylcytosine conjugates (ara-C) (1a, b and 2a, b) ofsn−1 andsn−3 isomers of 1-O-octadecyl-2-O-palmitoylglycerol and its 1-S-alkyl analogue have been synthesized, and their antitumor activity against L1210 lymphoid leukemia in mice were compared with those of the previous conjugates (3a, b) of racemates in order to determine the significance of chirality of the glycerol moieties for activity. Administration (i.p.) of a single dose (300 mg/kg) of conjugates ofsn−1 (1a),sn−3 (2a) andrac (3a) isomers of the ether lipid increased lifespan of i.p. implanted L1210 lymphoid leukemic DBA/2J mice by 169, 175 and 236%, respectively. Thesn−1 (1b),sn−3 (2b), andrac (3b) isomers of the thioether lipid with a single dose of 300 mg/kg produced an increase in lifespan values of 238, 263 and 250%, respectively. The results indicate that chirality of the glycerol moieties appears not to be critical for the activity, and racemates 3a and 3b are promising prodrugs of ara-C for further clinical investigations.

Synthesis and antitumor activity of 1-β-D-arabinofuranosylcytosine-5′-diphosphate-prednisolone and -cortisol

Superior antitumor activity and reduced toxicity of 1-β-arabinofuranosylcytosine (ara-C) conjugates of corticosteroids through a phosphodiester linkage have prompted us to synthesize the new ara-C conjugates of corticosteroids through a pyrophosphate diester linkage. Condensation of ara-CMP morpholidate with the steroid-21-monophosphates in pyridine at room temperature for 6 days and the subsequent separation on a DE-52 (formate) column using a linear gradient of 0−0.5 M triethylammonium formate (pH 7.0) gave ara-CDP-prednisolone (I) and ara-CDP-cortisol (II) in 37–55% yield. The conjugates were hydrolyzed to ara-CMP and the corresponding steroid-21-monophosphate by phosphodiesterase I. Conjugates I and II inhibited the in, vitro growth of L1210 lymphoid leukemia by 50% (ED50) at 0.03 and 0.08 μM, respectively, while ara-C and ara-CMP showed the respective ED50 of 0.1 μM and 0.05 μM. Conjugates I and II exhibited ILS values of 116 and 86%, respectively, at 40 mg (53.7 μmole)/kg/day × 5 against L1210 leukemic mice, while that of ara-C at the nearly same dose (49 μmole/kg/day × 5) was 65%.