Current medicinal chemistry
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The reductive conversion of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase (RR) is a crucial and rate-controlling step in the pathway leading to the biosynthesis of DNA, since deoxyribonucleotides are present in extremely low levels in mammalian cells. Mammalian ribonucleotide reductase (RR) is composed of two dissimilar proteins, often referred to as R(1), which contains polythiols and R(2), which contains non-heme iron and a free tyrosyl radical. Both the R(1) and R(2) subunits contribute to the active site of the enzyme. ⋯ More significantly, the ortho-phosphate prodrug 21 demonstrated impressive antitumor effect using once-a-day dosing regimen. In summary, the results disclosed herein demonstrated that some of 3-AP prodrugs prepared indeed demonstrated improved pharmaceutical, biological and toxicity profiles over the parent 3-AP. Efforts directed towards further optimization of 3-AP prodrugs as novel anticancer agents is clearly warranted.
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Cutaneous wound healing is a complex process involving interactions of various cell types. Skin, in addition to certain other organs, is dependent on estrogen; and estrogen-deficiency is associated with impaired wound healing. Wound healing involves the action of collagenolytic matrix metalloproteinases (MMPs). ⋯ Analysis of collagenolytic activity confirmed the decreased collagenolysis in skin wound extracts from CMT-treated rats when compared with skin wound extracts from OVX rats. Our results show for the first time that MMP-8 mRNA and protein are expressed in rat wound epithelium. We further show that CMT-8 and estrogen have a beneficial effect on skin wound healing in OVX rats by increasing the collagen content and reducing the MMP-mediated collagenolysis.
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Recent studies have demonstrated that tetracyclines can reduce bone loss in the ovariectomized (OVX) rat model of osteoporosis. In the current study, a non-antimicrobial, chemically modified doxycycline (CMT-8), alone or in combination with a bisphosphonate (Clodronate), was evaluated in this model. Forty-two, 6month old, female rats were randomly assigned to the following groups, (6/ group): a) sham/vehicle, b) OVX/vehicle; c) OVX/1 mg/day CMT-8; d) OVX/2 mg/day CMT-8, e) OVX/1 mg/week Clodronate; and f) OVX/1 mg/day CMT-8 + 1 mg/week Clodronate, CMT-8 was administered by oral gavage, Clodronate injected S/C. ⋯ In summary, CMT-8 mono-therapy (2 mg) alone partially inhibited bone loss in this animal model of osteoporosis. However, 1 mg/day (CMT-8) monotherapy had no effect on bone loss or bone mRNA levels and when combined with Clodronate, interacted to increase efficacy. Thus, a combination of a suboptimal dose of CMT-8 and a bisphosphonate appears to increase the amount of bone by suppressing resorption in a model of osteoporosis.