Structural Basis for Bifunctional Zinc(II) Macrocyclic Complex Recognition of Thymine Bulges in DNA

The zinc­(II) complex of 1-(4-quinoylyl)­methyl-1,4,7,10-tetraazacyclododecane (cy4q) binds selectively to thymine bulges in DNA and to a uracil bulge in RNA. Binding constants are in the low-micromolar range for thymine bulges in the stems of hairpins, for a thymine bulge in a DNA duplex, and for a uracil bulge in an RNA hairpin. Binding studies of Zn­(cy4q) to a series of hairpins containing thymine bulges with different flanking bases showed that the complex had a moderate selectivity for thymine bulges with neighboring purines. The dissociation constants of the most strongly bound Zn­(cy4q)–DNA thymine bulge adducts were 100-fold tighter than similar sequences with fully complementary stems or than bulges containing cytosine, guanine, or adenine. In order to probe the role of the pendent group, three additional zinc­(II) complexes containing 1,4,7,10-tetraazacyclododecane (cyclen) with aromatic pendent groups were studied for binding to DNA including 1-(2-quinolyl)­methyl-1,4,7,10-tetraazacyclododecane (cy2q), 1-(4-biphenyl)­methyl-1,4,7,10-tetraazacyclododecane (cybp), and 5-(1,4,7,10-tetraazacyclododecan-1-ylsulfonyl)-<i>N</i>,<i>N</i>-dimethylnaphthalen-1-amine (dsc). The Zn­(cybp) complex binds with moderate affinity but little selectivity to DNA hairpins with thymine bulges and to DNA lacking bulges. Similarly, Zn­(dsc) binds weakly both to thymine bulges and hairpins with fully complementary stems. The zinc­(II) complex of cy2q has the 2-quinolyl moiety bound to the Zn^II center, as shown by ¹H NMR spectroscopy and pH–potentiometric titrations. As a consequence, only weak (500 μM) binding is observed to DNA with no appreciable selectivity. An NMR structure of a thymine-bulge-containing hairpin shows that the thymine is extrahelical but rotated toward the major groove. NMR data for Zn­(cy4q) bound to DNA containing a thymine bulge is consistent with binding of the zinc­(II) complex to the thymine N3^– and stacking of the quinoline on top of the thymine. The thymine-bulge bound zinc­(II) complex is pointed into the major groove, and there are interactions with the guanine positioned 5′ to the thymine bulge

Highly Effective Dual-Function Near-Infrared (NIR) Photosensitizer for Fluorescence Imaging and Photodynamic Therapy (PDT) of Cancer

We report herein the synthesis and biological efficacy of near-infrared (NIR), bacteriochlorin analogues: 3-(1′-butyloxy)­ethyl-3-deacetyl-bacteriopurpurin-18-<i>N</i>-butylimide methyl ester (<b>3</b>) and the corresponding carboxylic acid <b>10</b>. In in vitro assays, compared to its methyl ester analogue <b>3</b>, the corresponding carboxylic acid derivative <b>10</b> showed higher photosensitizing efficacy. However, due to drastically different pharmacokinetics in vivo, the PS <b>3</b> (HPLC purity >99%) showed higher tumor uptake and long-term tumor cure than <b>10</b> (HPLC purity >96.5%) in BALB/c mice bearing Colon 26 tumors. Isomerically pure <i>R</i>- and <i>S</i>- isomers of <b>3</b> (<b>3a</b> and <b>3b</b>, purity by HPLC > 99%) under similar treatment parameters showed identical efficacy in vitro and in vivo. In addition, photosensitizer (PS) <b>3</b> showed limited skin phototoxicity and provides an additional advantage over the clinically approved chemically complex hematoporphyrin derivative as well as other porphyrin-based PDT agents, which makes <b>3</b> a promising dual-function agent for fluorescence-guided surgery with an option of phototherapy of cancer

Highly Effective Dual-Function Near-Infrared (NIR) Photosensitizer for Fluorescence Imaging and Photodynamic Therapy (PDT) of Cancer

We report herein the synthesis and biological efficacy of near-infrared (NIR), bacteriochlorin analogues: 3-(1′-butyloxy)­ethyl-3-deacetyl-bacteriopurpurin-18-<i>N</i>-butylimide methyl ester (<b>3</b>) and the corresponding carboxylic acid <b>10</b>. In in vitro assays, compared to its methyl ester analogue <b>3</b>, the corresponding carboxylic acid derivative <b>10</b> showed higher photosensitizing efficacy. However, due to drastically different pharmacokinetics in vivo, the PS <b>3</b> (HPLC purity >99%) showed higher tumor uptake and long-term tumor cure than <b>10</b> (HPLC purity >96.5%) in BALB/c mice bearing Colon 26 tumors. Isomerically pure <i>R</i>- and <i>S</i>- isomers of <b>3</b> (<b>3a</b> and <b>3b</b>, purity by HPLC > 99%) under similar treatment parameters showed identical efficacy in vitro and in vivo. In addition, photosensitizer (PS) <b>3</b> showed limited skin phototoxicity and provides an additional advantage over the clinically approved chemically complex hematoporphyrin derivative as well as other porphyrin-based PDT agents, which makes <b>3</b> a promising dual-function agent for fluorescence-guided surgery with an option of phototherapy of cancer

Highly Effective Dual-Function Near-Infrared (NIR) Photosensitizer for Fluorescence Imaging and Photodynamic Therapy (PDT) of Cancer

We report herein the synthesis and biological efficacy of near-infrared (NIR), bacteriochlorin analogues: 3-(1′-butyloxy)­ethyl-3-deacetyl-bacteriopurpurin-18-<i>N</i>-butylimide methyl ester (<b>3</b>) and the corresponding carboxylic acid <b>10</b>. In in vitro assays, compared to its methyl ester analogue <b>3</b>, the corresponding carboxylic acid derivative <b>10</b> showed higher photosensitizing efficacy. However, due to drastically different pharmacokinetics in vivo, the PS <b>3</b> (HPLC purity >99%) showed higher tumor uptake and long-term tumor cure than <b>10</b> (HPLC purity >96.5%) in BALB/c mice bearing Colon 26 tumors. Isomerically pure <i>R</i>- and <i>S</i>- isomers of <b>3</b> (<b>3a</b> and <b>3b</b>, purity by HPLC > 99%) under similar treatment parameters showed identical efficacy in vitro and in vivo. In addition, photosensitizer (PS) <b>3</b> showed limited skin phototoxicity and provides an additional advantage over the clinically approved chemically complex hematoporphyrin derivative as well as other porphyrin-based PDT agents, which makes <b>3</b> a promising dual-function agent for fluorescence-guided surgery with an option of phototherapy of cancer