High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin.

Abstract

A convenient, high yield conversion of doxorubicin to 3'-deamino-3'-(2''-pyrroline-1''-yl)doxorubicin is described. This daunosamine-modified analog of doxorubicin is 500-1000 times more active in vitro than doxorubicin. The conversion is effected by using a 30-fold excess of 4-iodobutyraldehyde in anhydrous dimethylformamide. The yield is higher than 85%. A homolog of this compound, 3'-deamino-3'-(1'',3''-tetrahydropyridine-1''-yl)doxorubicin, was also synthesized by using 5-iodovaleraldehyde. In this homolog, the daunosamine nitrogen is incorporated into a six- instead of a five-membered ring. This analog was 30-50 times less active than its counterpart with a five-membered ring. A similar structure-activity relationship was found when 3'-deamino-3'-(3''-pyrrolidone-1''-yl)doxorubicin (containing a five-membered ring) and 3'-deamino-3'-(3''-piperidone-1''-yl)doxorubicin (with a six-membered ring) were tested in vitro, the former being 5 times more potent than the latter. To further elucidate structure-activity relationships, 3'-deamino-3'-(pyrrolidine-1''-yl)doxorubicin, 3'-deamino-3'-(isoindoline-2''-yl)doxorubicin, 3'-deamino-3'-(2''-methyl-2''-pyrroline-1''-yl)doxorubicin, and 3'-deamino-3'-(3''-pyrroline-1''-yl)doxorubicin were also synthesized and tested. All the analogs were prepared by using reactive halogen compounds for incorporating the daunosamine nitrogen of doxorubicin into a five- or six-membered ring. These highly active antineoplastic agents can be used for incorporation into targeted cytotoxic analogs of luteinizing hormone-releasing hormone intended for cancer therapy.

Recovery of pituitary function after treatment with a targeted cytotoxic analog of luteinizing hormone-releasing hormone

“…Recently, we developed a series of highly active derivatives of doxorubicin (DOX) (17). Among them, 2-pyrrolino-DOX (AN-201) showed a potency 500-1000 times higher in vitro than its parent compound (17).…”

Growth inhibition of experimental non‐Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue AN‐238

“…18,19 AN-238 was made by coupling AN-201-14-O-hemiglutarate to the NH 2 terminus of [Lys-(N-(9-fluorenyl)methoxycarbonyl) 5 ]RC-121, followed by deprotection and purification. 17 For i.v.…”

“…17 AN-238 consists of the carrier somatostatin octapeptide RC-121 linked covalently to a highly potent derivate of DOX, AN-201. 18 This analogue fully retains the cytotoxic activity of the radical and binds with high affinity to somatostatin receptor subtypes sst 2 and sst 5 and with medium affinity to subtype sst 3 . AN-238 significantly inhibits the growth of various tumors that express somatostatin receptors (subtypes 2, 3 and 5).…”

Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215

“…The presence of high affinity receptors for bombesin (BN)-like peptides on a wide variety of tumours prompted us to employ some of our powerful BN/gastrin releasing peptide (GRP) antagonists as carrier molecules for targeting cytotoxic agents to tumour cells (Nagy et al, 1997). One of these cytotoxic BN conjugates, AN-215 (Nagy et al, 1997) consists of a potent cytotoxic derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201) (Nagy et al, 1996), covalently linked through a glutaric acid spacer to the amino terminal of Gln-Trp-Ala-Val-Gly-His-Leu-c-Leu-NH 2, a BN-like peptide carrier (Nagy et al, 1997). AN-215 displays high affinity to BN receptors on Swiss 3T3 fibroblasts and retains the antiproliferative effect of its cytotoxic moiety (Nagy et al, 1997).…”

“…GRP(14-27), cytotoxic radical AN-201 (Nagy et al, 1996) and BN/GRP antagonist RC-3095 [D-Tpi 6 ,Leu 13 c(CH 2 NH)Leu 14 ]BN (6-14) (Radulovic et al, 1991) were also synthesised in our laboratory. For intravenous (i.v.)…”