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Abstract
A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the cycloaddition reaction of nitrogen-containing 1,3-binucleophiles with the steroidal α,β-unsaturated ketone. Urea, thiourea and guanidine reacted in a similar manner and afforded the steroidal pyrimidines in good yields. The antiproliferative tests against human tumor cell lines gave GI50 values in the micromolar range and had no effect on healthy fibroblasts. Additional experiments indicated that the compounds did not act as P-glycoprotein substrates, thus avoiding the rise of drug resistance. The fused steroidal pyrimidinethione was selected as drug lead for further testing due to its strong antiproliferative activities within the low micromolar range.
Highlights
The direct use of natural products as drugs is limited because their physicochemical properties are often far from ideal
We studied the antiproliferative activity of α,β-unsaturated ketones (2 and 6) and steroidal pyrimidines (3 and 7) against human cell lines following the guidelines of the National Cancer
Pregnenolone acetate (1) and diosgenin (4) were efficiently transformed into α,β-unsaturated ketones 2 and 6, respectively. These intermediates were treated with 1,3-binucleophiles to produce steroidal pyrimidines 3 and 7, respectively
Summary
The direct use of natural products as drugs is limited because their physicochemical properties are often far from ideal. They represent an excellent starting point in drug discovery programs. When considering the chemical structure of small-molecule approved drugs, 59% of them contain a nitrogen heterocycle [4]. From this subset, six-membered rings (59%) are the most common, followed by five-membered (39%) and fused rings (14%). Pyrimidine approved drugs are used for the treatment of three main disease classes: anti-infective, cardiovascular, and oncological. It has been reported that the conjugation of a pyrimidine moiety with a steroidal framework resulted in a synergistic effect of both biologically active molecular scaffolds providing new compounds with antiproliferative [5,6,7,8,9] (Figure 1), antioxidant [10], anti-Alzheimer [11], or antibacterial properties [12]
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