Synthesis of hydroxy- and amino-substituted benzohydroxamic acids: inhibition of ribonucleotide reductase and antitumor activity

Abstract

Benzohydroxamic acids inhibit mammalian ribonucleotide reductase and exhibit antineoplastic activity in L1210 leukemic mice. Five new hydroxy- and amino-substituted benzohydroxamic acids (3,4- and 3,5-OH, 3,4-NH2, 2,3,4- and, 3,4,5-OH) were prepared and tested along with 12 previously reported benzohydroxamic acids (BHA) for enzyme inhibition and antitumor activity. The most potent enzyme inhibitor in this series was 2,3,4-OH-BHA (ID50 = 3.5 microM), which is 140 times more potent than hydroxyurea, but its toxicity limited the antitumor activity to a 30% increase in life span of L1210 bearing mice at 125 (mg/kg)/day ip for 8 days. The most effective antitumor agent in this series was 3,4-OH-BHA which prolonged the life span of L1210 bearing mice 103% at 600 (mg/kg)/day ip for 8 days.

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

“…To date, no serious side effects have been reported with didox treatment even when administered for long periods (21). Didox has been shown to inhibit proliferation of several cancer cell types (18)(19)(20)45) and modulate other cancer chemotherapeutic agents resulting in elevated apoptosis (42). Didox was also shown to synergize with temozolomide in brain tumors and with doxorubicin in liver cancer cells (46,47).…”

“…RRM2 is an attractive target for combination therapy, as it is overexpressed in breast cancer and contributes to development of resistance (11). Didox (3,4-dihydroxybenzohydroxamic acid) is a strong inhibitor of ribonucleotide reductase that interferes with DNA synthesis and repair by blocking the production of deoxyribonucleotides and has demonstrated antitumor effects for decades (12,(18)(19)(20). Phase I/II clinical trial studies in patients with cancer showed minimal toxicity and determined that the maximum tolerated dose of didox is 6 g/m 2 , yielding peak plasma levels of 425 mmol/L (21,22).…”

Ribonucleotide reductase inhibitors enhance cidofovir‐induced apoptosis in EBV‐positive nasopharyngeal carcinoma xenografts

“…Didox is a polyhydroxysubstituted benzohydroxamic acid derivative that belongs to a new class of RR inhibitors. 34 It has been suggested that didox-induced RR inhibition is due to the reversible destruction of the R2 tyrosil free radical, as demonstrated for hydroxyurea. 11 However, other results suggest that didox has some other properties.…”

A phase I and pharmacokinetic study of didox administered by 36 hour infusion

“…Didox causes greater inhibition of the target enzyme (Elford et al, 1979) and in view of its in vivo activity was entered in phase I evaluation, as part of a co-ordinated programme under the aegis of the Cancer Research Campaign Phase I/II Clinical Trials Committee. It was initially administered by intravenous infusion over 30 min (Veale et al, 1988b).…”

“…Didox causes greater inhibition of the target enzyme (Elford et al, 1979) Analytical methods Didox levels were measured in plasma and urine by HPLC using a Beckman/Altex IOOA pump and stainless steel column (15 cm x 0.46 cm) packed with a A-Bondapack C18, 10 jim particle size, as previously described (Veale et al, 1988). Metabolites were identified using standards supplied by Elford.…”