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Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors.

Lee CL, Lin YT, Chang FR, Chen GY, Backlund A, Yang JC, Chen SL, Wu YC - PLoS ONE (2012)

Bottom Line: The SAR for moderately active 5a-b (5-OCH(3)), and highly active 6a-b and 7a-b, are also elaborated in a spatial aspect model.Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model.Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a-b as topoisomerase II inhibitors.

View Article: PubMed Central - PubMed

Affiliation: School of Chinese Medicine, China Medical University, Taichung, Taiwan.

ABSTRACT
In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC(50) 0.08-1.66 µg/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer cell line. The pharmacophore model indicates that HBA3 is an essential feature for the oxygen atom of 5-OH in 6a-b and for the carbonyl group of 5-OCOCH(3) in 7a-b, important for their cytotoxic properties. The SAR for moderately active 5a-b (5-OCH(3)), and highly active 6a-b and 7a-b, are also elaborated in a spatial aspect model. Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model. Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a-b as topoisomerase II inhibitors.

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Synthetic procedure of phenanthrene derivatives.Reagents and conditions: (i) DDQ, benzene, RT. (ii) TFA, ether, RT. (iii) Me2SO4, K2CO3, acetone, reflux. (iv) P4-tBu, benzene, 140°C. (v) AgO, 6 N HNO3, acetone, 60°C.
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pone-0037897-g003: Synthetic procedure of phenanthrene derivatives.Reagents and conditions: (i) DDQ, benzene, RT. (ii) TFA, ether, RT. (iii) Me2SO4, K2CO3, acetone, reflux. (iv) P4-tBu, benzene, 140°C. (v) AgO, 6 N HNO3, acetone, 60°C.

Mentions: We modified the synthetic procedure of Dr. Kraus and his co-workers [12], [13] to synthesize all phenanthrene derivatives. As shown in Figure 3, 2-aldehyde-1,4-quinone was prepared by DDQ oxidation of commercially available 2,5-dihydroxybenzaldehyde. The quinone was coupled with 3,4,5-trimethoxytoluene and 3,5-dimethoxytoluene in the presence of 1 equivalent of trifluoroacetic acid to produce 1a and 1b, respectively. Compounds 1a and 1b were methylated with Me2SO4 in the presence of K2CO3 (acetone, 60°C, 5 h) to give the desired 2a and 2b. Cyclization of 2a and 2b with P4-tBu (benzene, 110 or 140°C, 19–29 h) gave phenanthrenes 3a and 3b, which were oxidized with AgO (6 N HNO3, acetone, 50°C, 2–3 min) to phenanthrenequinone 4a, 4b and 4c. Addition of methanol to 4a, 4b and 4c catalyzed by ferric sulfate [14] gave 5a–f, respectively (Figure 4). Compounds 7a and 7b were obtained by treatment of 5a and 5b with TMSI (CH2Cl2, RT or 60°C, monitored by TLC) to give calanquinone A (6a; CA-1) and denbinobin (6b), followed by treatment with Ac2O (pyridine, RT, overnight) to selectively remove the methyl group and incorporate an acetyl group at C-5, respectively (Figure 5). It is a characteristic feature of the angular arrangement of 1,4-phenanthrenequinones which led to remarkable selectivity in the cleavage of sterically hindered methyl ether at C-5 even in preference of that at C-3. However, applying TMSI to remove the methyl groups in phenanthrenes 3a and 3b was unsuccessful. Finally, cleavage of the methyl ether groups in 3a and 3b with AlCl3 generated compounds 8a & 9a and 8b & 9b, respectively (Figure 6). The excess AlCl3 regioselectively cleaved the methyl ethers only at C-4 and C-5 or C-6 in order to release the steric strain.


Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors.

Lee CL, Lin YT, Chang FR, Chen GY, Backlund A, Yang JC, Chen SL, Wu YC - PLoS ONE (2012)

Synthetic procedure of phenanthrene derivatives.Reagents and conditions: (i) DDQ, benzene, RT. (ii) TFA, ether, RT. (iii) Me2SO4, K2CO3, acetone, reflux. (iv) P4-tBu, benzene, 140°C. (v) AgO, 6 N HNO3, acetone, 60°C.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3362575&req=5

pone-0037897-g003: Synthetic procedure of phenanthrene derivatives.Reagents and conditions: (i) DDQ, benzene, RT. (ii) TFA, ether, RT. (iii) Me2SO4, K2CO3, acetone, reflux. (iv) P4-tBu, benzene, 140°C. (v) AgO, 6 N HNO3, acetone, 60°C.
Mentions: We modified the synthetic procedure of Dr. Kraus and his co-workers [12], [13] to synthesize all phenanthrene derivatives. As shown in Figure 3, 2-aldehyde-1,4-quinone was prepared by DDQ oxidation of commercially available 2,5-dihydroxybenzaldehyde. The quinone was coupled with 3,4,5-trimethoxytoluene and 3,5-dimethoxytoluene in the presence of 1 equivalent of trifluoroacetic acid to produce 1a and 1b, respectively. Compounds 1a and 1b were methylated with Me2SO4 in the presence of K2CO3 (acetone, 60°C, 5 h) to give the desired 2a and 2b. Cyclization of 2a and 2b with P4-tBu (benzene, 110 or 140°C, 19–29 h) gave phenanthrenes 3a and 3b, which were oxidized with AgO (6 N HNO3, acetone, 50°C, 2–3 min) to phenanthrenequinone 4a, 4b and 4c. Addition of methanol to 4a, 4b and 4c catalyzed by ferric sulfate [14] gave 5a–f, respectively (Figure 4). Compounds 7a and 7b were obtained by treatment of 5a and 5b with TMSI (CH2Cl2, RT or 60°C, monitored by TLC) to give calanquinone A (6a; CA-1) and denbinobin (6b), followed by treatment with Ac2O (pyridine, RT, overnight) to selectively remove the methyl group and incorporate an acetyl group at C-5, respectively (Figure 5). It is a characteristic feature of the angular arrangement of 1,4-phenanthrenequinones which led to remarkable selectivity in the cleavage of sterically hindered methyl ether at C-5 even in preference of that at C-3. However, applying TMSI to remove the methyl groups in phenanthrenes 3a and 3b was unsuccessful. Finally, cleavage of the methyl ether groups in 3a and 3b with AlCl3 generated compounds 8a & 9a and 8b & 9b, respectively (Figure 6). The excess AlCl3 regioselectively cleaved the methyl ethers only at C-4 and C-5 or C-6 in order to release the steric strain.

Bottom Line: The SAR for moderately active 5a-b (5-OCH(3)), and highly active 6a-b and 7a-b, are also elaborated in a spatial aspect model.Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model.Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a-b as topoisomerase II inhibitors.

View Article: PubMed Central - PubMed

Affiliation: School of Chinese Medicine, China Medical University, Taichung, Taiwan.

ABSTRACT
In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC(50) 0.08-1.66 µg/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer cell line. The pharmacophore model indicates that HBA3 is an essential feature for the oxygen atom of 5-OH in 6a-b and for the carbonyl group of 5-OCOCH(3) in 7a-b, important for their cytotoxic properties. The SAR for moderately active 5a-b (5-OCH(3)), and highly active 6a-b and 7a-b, are also elaborated in a spatial aspect model. Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model. Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a-b as topoisomerase II inhibitors.

Show MeSH
Related in: MedlinePlus