balaji babu - Academia.edu (original) (raw)
Papers by balaji babu
A convenient synthesis of some acetylene-tethered chiral and achiral dialdehydes using Sonagashir... more A convenient synthesis of some acetylene-tethered chiral and achiral dialdehydes using Sonagashira-Hagihara coupling has been accomplished. Dibromobenzenes and enantiopure dibromobinaphthol were functionalized to provide the acetylene-tethered dialdehydes in moderate to good yields.
Bioorganic & Medicinal Chemistry Letters, 2015
The design, synthesis, and DNA binding properties of azaHx-PI or p-anisyl-4-aza-benzimidazolepyrr... more The design, synthesis, and DNA binding properties of azaHx-PI or p-anisyl-4-aza-benzimidazolepyrrole-imidazole (5) are described. AzaHx, 2-(p-anisyl)-4-aza-benzimidazole-5-carboxamide, is a novel, fluorescent DNA recognition element, derived from Hoechst 33258 to recognize G•C base pairs. Supported by theoretical data, the results from DNase I footprinting, CD, T M , and SPR studies provided evidence that an azaHx/IP pairing, formed from antiparallel stacking of two azaHx-PI molecules in a side-by-side manner in the minor groove, selectively recognized a C-G doublet. AzaHx-PI was found to target 5'-ACGCGT-3', the Mlu1 Cell Cycle Box (MCB) promoter sequence with specificity and significant affinity (K eq 4.0 ± 0.2 x 10 7 M-1).
ChemInform, 2004
Oxidation of I-alkyl/aralky 1-2-(a-hydrox yalky l/ary I)benzimidazo les 1 with KMn04 on neutral a... more Oxidation of I-alkyl/aralky 1-2-(a-hydrox yalky l/ary I)benzimidazo les 1 with KMn04 on neutral alumina under solid phase condition s gives the corresponding ketones, l-alkyl/aralkyl-2-acy lbenzimidazoles 2. Compound 2a (R 2 = CH 3) on condensation with aromatic aldehydes in the presence of solid NaOH under solvent-free conditions, yields the corresponding chalcones, 1alkyl/aralkyl-2-benzimidazole ary l vinyl keto ne 3. Aldehydes and ketones are found to be very good reactive intermediates. Numerous methods have been reported I in the literature to synthesize carbonyl compounds from primary and secondary alcohols. One of these methods 2 involves solid phase oxidation using
Synthetic Communications, 2014
ABSTRACT Pyrrole- and imidazole-containing polyamides can be tailored to recognize the DNA 6–8 ba... more ABSTRACT Pyrrole- and imidazole-containing polyamides can be tailored to recognize the DNA 6–8 base pair sequence. We found that adding a second amino group via the N1-position of pyrrole or imidazole in polyamides could enhance their DNA binding affinity and water solubility while retaining sequence specificity. Synthesis of the key 1-substituted-4-nitropyrrole (and imidazole)-2-carboxylic acid building blocks are described.[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]
Medicinal Chemistry Research, 2009
Seven novel analogs of 1-phenylethanolamine carboxamide derivatives, 3a-g, related to carboxamide... more Seven novel analogs of 1-phenylethanolamine carboxamide derivatives, 3a-g, related to carboxamides isolated from Isodon excisus were synthesized and evaluated for their cytotoxic and apoptosis-induction properties against murine B16 and leukemia L1210 cell lines. Compounds containing no substitution at the 4'-position (3a-d) or containing a 4'-amino (3e-g) group were investigated. Generally, the amino-containing compounds were slightly more active than their unsubstituted congeners. Also, the indole-containing compounds 3c and 3f gave the strongest cytotoxic activity (IC 50 25-87 µM) against the growth of L1210 and B16 cancer cells. Compound 3f was subjected to flow cytometry studies and it was found to induce L1210 cells grown in culture to undergo apoptosis.
Medicinal Chemistry, 2010
N-Methyl imidazole (Im) and N-methyl pyrrole (Py)-containing polyamides that can form stacked dim... more N-Methyl imidazole (Im) and N-methyl pyrrole (Py)-containing polyamides that can form stacked dimers can be programmed to target specific DNA sequences in the minor groove of DNA and control gene expression. Polyamides are being investigated as potential medicinal agents for treating diseases including cancer. The naturally occurring polyamide distamycin binds as a dimer in the minor groove of DNA and recognizes sequences rich in A/T and T/A base pairs indiscriminately. Synthetic analogs of distamycin that incorporate N-methylimidazole into the heterocyclic core have been shown to bind to G/C rich sequences with a high degree of specificity. The purpose of this study is to investigate the behavior of polyamides containing the 2,5-linked N-methylpyrrole-2-carboxamide or pyrrole(H) [Py(H)] moiety upon binding to DNA. The synthesis and biophysical characteristics of two polyamides PyPyPyPy(H) 2 and ImPyPyPy(H) 3 designed to test the binding preference of a Py/Pyrrole(H) pairing [Py/Py(H)] and a [Im/Py(H)] is described. Studies utilizing circular dichroism, thermal denaturation (ΔT M), biosensor-surface plasmon resonance and DNase I footprinting show that an [Im/Py(H), 3]
Heterocyclic Communications, 2010
The biophysical and biological evaluations of DNA minor groove binding AT sequence selective benz... more The biophysical and biological evaluations of DNA minor groove binding AT sequence selective benzimidazole analogs of Hoechst 33258 which contain a p-anisyl, a p-[bis(2-chloroethyl)amino]phenyl or a p-anisyl and an amidine moiety are discussed. The preference for all three compounds for the 5 ′-AAATTT-3 ′ sequence was ascertained by thermal denaturation and circular dichroism studies. The mustard-containing compound 4 was found to be more cytotoxic against murine cancer cells grown in culture than the non-mustard containing compound. DNA alkylation was not necessary for anti-Leishmanial activity.
Chemical Biology & Drug Design, 2011
Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyc... more Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyclic ketones were designed, synthesized, and investigated for cytotoxicity against murine B16 and L1210 cancer cell lines. The analogs belong to four structurally divergent series, three of which (series g, h, and i) contain differently substituted cyclopentanone units and the fourth (series j) contains a 3,3-dimethyl-4-piperidinone moiety. Of these, the analogs in series j showed potential cytotoxic activity against murine B16 (melanoma) and L1210 (lymphoma) cells. The most active compounds 5j, 11j, 15j, and 12h produced IC 50 values from 4.4 to 15 lM against both cell lines. A singlecrystal X-ray structure analysis and molecular modeling studies confirmed that these chalcones have an E-geometry about the alkene bond and possess a slightly 'twisted' conformation similar to that of combretastatin A-4. At a concentration of 30 lM, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action.
Biopolymers, 2013
Synthetic N-methyl imidazole and N-pyrrole containing polyamides (PAs) that can form "stacked" di... more Synthetic N-methyl imidazole and N-pyrrole containing polyamides (PAs) that can form "stacked" dimers can be programmed to target and bind to specific DNA sequences and control gene expression. To accomplish this goal, the development of PAs with lower molecular mass which allows for the molecules to rapidly penetrate cells and localize in the nucleus, along with increased water solubility, while maintaining DNA binding sequence specificity and high binding affinity is key. To meet these challenges, six novel f-ImPy*Im PA derivatives that contain different orthogonally positioned moieties were designed to target 5′-ACGCGT-3′. The synthesis and biophysical characterization of six f-ImPy*Im were determined by CD, ΔT M , DNase I footprinting, SPR, and ITC studies, and were compared with those of their parent compound, f-ImPyIm. The results gave evidence for the minor groove binding and selectivity of PAs 1 and 6 for the cognate sequence 5′-ACGCGT-3′, and with strong affinity, K eq = 2.8 × 10 8 M −1 and K eq = 6.2 × 10 7 M −1 , respectively. The six novel PAs presented in this study demonstrated increased water solubility, while maintaining low molecular mass, sequence specificity, and binding affinity, addressing key issues in therapeutic development.
Bioorganic & Medicinal Chemistry Letters, 2013
Bioorganic & Medicinal Chemistry, 2013
Orthogonally positioned diamino/dicationic polyamides (PAs) have good water solubility and enhanc... more Orthogonally positioned diamino/dicationic polyamides (PAs) have good water solubility and enhanced binding affinity, whilst retaining DNA minor groove and sequence specificity compared to their monoamino/monocationic counterparts. The synthesis and DNA binding properties of the following diamino PAs: f-IPI (3a), f-IPP (4), f-PIP (5), and f-PPP (6) are described. P denotes the site where a 1-propylamino group is attached to the N1-position of the heterocycle. Binding of the diamino PAs to DNA was assessed by DNase I footprinting, thermal denaturation, circular dichroism titration, biosensor surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) studies. According to SPR studies, f-IPI (3a) bound more strongly (K eq = 2.4 Â 10 8 M À1) and with comparable sequence selectivity to its cognate sequence 5 0-ACGCGT-3 0 when compared to its monoamino analog f-IPI (1). The binding of f-IPI (3a) to 5 0-ACGCGT-3 0 via the stacked dimer motif was balanced between enthalpy and entropy, and that was quite different from the enthalpy-driven binding of its monoamino parent f-IPI (1). f-IPP (4) also bound more strongly to its cognate sequence 5 0-ATGCAT-3 0 (K eq = 7.4 Â 10 6 M À1) via the side-by-side stacked motif than its monoamino analog f-IPP (2a). Although f-PPP (6) bound via a 1:1 motif, it bound strongly to its cognate sequence 5 0-AAATTT-3 0 (K eq = 4.8 Â 10 7 M À1), 15-times higher than the binding of its monoamino analog f-PPP (2c), albeit f-PPP bound via the stacked motif. Finally, f-PIP (5) bound to its target sequence 5 0-ATCGAT-3 0 as a stacked dimer and it has the lowest affinity among the diamino PAs tested (K eq <1 Â 10 5 M À1). This was about two times lower in affinity than the binding of its monoamino analog f-PIP (2b). The results further demonstrated that the 'core rules' of DNA recognition by monoamino PAs also apply to their diamino analogs. Specifically, PAs that contain a stacked IP core structure bind most strongly (highest binding constants) to their cognate GC doublet, followed by the binding of PAs with a stacked PP structure to two degenerate AT base pairs, and finally the binding of PAs with a PI core to their cognate CG doublet.
Bioorganic & Medicinal Chemistry, 2012
Pyrrole- and imidazole-containing polyamides are widely investigated as DNA sequence selective bi... more Pyrrole- and imidazole-containing polyamides are widely investigated as DNA sequence selective binding agents that have potential use as gene control agents. The key challenges that must be overcome to realize this goal is the development of polyamides with low molar mass so the molecules can readily diffuse into cells and concentrate in the nucleus. In addition, the molecules must have
![Research paper thumbnail of A novel achiral seco-cyclopropylpyrido[e]indolone (CPyI) analog of CC-1065 and the duocarmycins: Synthesis, DNA interactions, in vivo anticancer and anti-parasitic evaluation](https://attachments.academia-assets.com/88820170/thumbnails/1.jpg)
](Bioorganic & Medicinal Chemistry, 2010
The synthesis of an achiral seco-hydroxy-aza-CBI-TMI analog (8) of the duocarmycins is reported. ... more The synthesis of an achiral seco-hydroxy-aza-CBI-TMI analog (8) of the duocarmycins is reported. Its specificity for the DNA minor groove of AT-rich sequences and covalent bonding to adenine-N3 was ascertained by a thermal cleavage assay. Compound 8 was found to be cytotoxic in the nanomolar range against murine and human cancer cells. It was further demonstrated that compound 8 was active against murine melanoma (B16-F0) grown in C57BL/6 mice. Compound 8 was also shown to inhibit the growth of the protozoan parasites Leishmania donovani, Leishmania Mexicana, Trypanosoma brucei, and Plasmodium falciparum in culture.
Biochemistry, 2011
P yrrole (P) and imidazole (I)-containing polyamide analogues of the naturally occurring distamyc... more P yrrole (P) and imidazole (I)-containing polyamide analogues of the naturally occurring distamycin A (1) bind in the minor groove of DNA in a stacked, antiparallel 2:1 (ligand/DNA) motif. 1À3 Early studies have led to the establishment of a set of pairing rules for DNA base pair recognition; a P/P stacking recognizes an A/T or T/A base pair, an I/P stacking binds to a G/C base pair, while a P/I stacking recognizes a C/G base pair. In addition, a stacked I/I pairing targets a T/G mismatch. 4À6 As a result of the high degree of sequence specificity that these molecules exhibit, their potential use as regulators of gene expression has been widely explored. 7 However, attempts to inhibit the transcription of genes that code for a disease in cell lines have been met with moderate success which presumably points toward poor cellular uptake of some of these polyamides and their limited ability to achieve nuclear localization. 8,9 Some success in this area has been achieved through the attachment of
Heterocyclic Communications, 2010
Hairpin polyamide analogs of distamycin A (1) were designed and synthesized to evaluate their abi... more Hairpin polyamide analogs of distamycin A (1) were designed and synthesized to evaluate their ability to bind 5 ′-ATAGA-3 ′ and 5 ′-AGATA-3 ′ sequences which are important elements for controlling the function of the Brn-3b and GATA-3 transcriptional factors, respectively. The hairpin polyamides are composed of pyrrole and imidazole units linked together via a γ-aminobutyrate (GABA) unit. Hairpins 2b (Py-Py-Im-γ-Py-Py-Py) and 2c (Im-Py-Py-γ-Py-Py-Py) were synthesized to target the respective Brn-3b and GATA-3 cognate sequences. Preliminary biophysical studies including thermal denaturation and circular dichroism were performed and the results ascertained the binding of hairpins 2a and 2b to their respective cognate DNA sequences.
Medicinal Chemistry Research, 2011
Eighteen 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs (5a-j, 6a-e, and 7a-c) of combretastatin A... more Eighteen 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs (5a-j, 6a-e, and 7a-c) of combretastatin A-4 were synthesized with the objective of discovering compounds capable of controlling the growth of Trypanosoma lewisii, Leishmania tarantole, Plasmodium falciparum, and Giardia lamblia. Even though the target compounds demonstrated differential cytotoxicity against mammalian cancer cells, with IC 50 values ranging from 0.5 to [100 lM, the range of activity against Trypanosoma, Leishmania, and Plasmodium, and to a good extent for Giardia, was narrow. The IC 50 values of ''active'' compounds against the parasites ranged from about 10 lL to slightly greater than 50 lL. Specifically, compounds 5a, 5g, 5h, 6c, 7a, and 7c were not cytotoxic against mammalian cancer cells (IC 50 [ 100 lM) but showed good activity against the parasites, except Giardia (e.g., compounds 6c and 7a), suggesting that these compounds may act in a similar mechanism in parasites. Compounds 5f and 6b were previously shown to promote microtubule depolymerization in mammalian cells.
A convenient synthesis of some acetylene-tethered chiral and achiral dialdehydes using Sonagashir... more A convenient synthesis of some acetylene-tethered chiral and achiral dialdehydes using Sonagashira-Hagihara coupling has been accomplished. Dibromobenzenes and enantiopure dibromobinaphthol were functionalized to provide the acetylene-tethered dialdehydes in moderate to good yields.
Bioorganic & Medicinal Chemistry Letters, 2015
The design, synthesis, and DNA binding properties of azaHx-PI or p-anisyl-4-aza-benzimidazolepyrr... more The design, synthesis, and DNA binding properties of azaHx-PI or p-anisyl-4-aza-benzimidazolepyrrole-imidazole (5) are described. AzaHx, 2-(p-anisyl)-4-aza-benzimidazole-5-carboxamide, is a novel, fluorescent DNA recognition element, derived from Hoechst 33258 to recognize G•C base pairs. Supported by theoretical data, the results from DNase I footprinting, CD, T M , and SPR studies provided evidence that an azaHx/IP pairing, formed from antiparallel stacking of two azaHx-PI molecules in a side-by-side manner in the minor groove, selectively recognized a C-G doublet. AzaHx-PI was found to target 5'-ACGCGT-3', the Mlu1 Cell Cycle Box (MCB) promoter sequence with specificity and significant affinity (K eq 4.0 ± 0.2 x 10 7 M-1).
ChemInform, 2004
Oxidation of I-alkyl/aralky 1-2-(a-hydrox yalky l/ary I)benzimidazo les 1 with KMn04 on neutral a... more Oxidation of I-alkyl/aralky 1-2-(a-hydrox yalky l/ary I)benzimidazo les 1 with KMn04 on neutral alumina under solid phase condition s gives the corresponding ketones, l-alkyl/aralkyl-2-acy lbenzimidazoles 2. Compound 2a (R 2 = CH 3) on condensation with aromatic aldehydes in the presence of solid NaOH under solvent-free conditions, yields the corresponding chalcones, 1alkyl/aralkyl-2-benzimidazole ary l vinyl keto ne 3. Aldehydes and ketones are found to be very good reactive intermediates. Numerous methods have been reported I in the literature to synthesize carbonyl compounds from primary and secondary alcohols. One of these methods 2 involves solid phase oxidation using
Synthetic Communications, 2014
ABSTRACT Pyrrole- and imidazole-containing polyamides can be tailored to recognize the DNA 6–8 ba... more ABSTRACT Pyrrole- and imidazole-containing polyamides can be tailored to recognize the DNA 6–8 base pair sequence. We found that adding a second amino group via the N1-position of pyrrole or imidazole in polyamides could enhance their DNA binding affinity and water solubility while retaining sequence specificity. Synthesis of the key 1-substituted-4-nitropyrrole (and imidazole)-2-carboxylic acid building blocks are described.[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]
Medicinal Chemistry Research, 2009
Seven novel analogs of 1-phenylethanolamine carboxamide derivatives, 3a-g, related to carboxamide... more Seven novel analogs of 1-phenylethanolamine carboxamide derivatives, 3a-g, related to carboxamides isolated from Isodon excisus were synthesized and evaluated for their cytotoxic and apoptosis-induction properties against murine B16 and leukemia L1210 cell lines. Compounds containing no substitution at the 4'-position (3a-d) or containing a 4'-amino (3e-g) group were investigated. Generally, the amino-containing compounds were slightly more active than their unsubstituted congeners. Also, the indole-containing compounds 3c and 3f gave the strongest cytotoxic activity (IC 50 25-87 µM) against the growth of L1210 and B16 cancer cells. Compound 3f was subjected to flow cytometry studies and it was found to induce L1210 cells grown in culture to undergo apoptosis.
Medicinal Chemistry, 2010
N-Methyl imidazole (Im) and N-methyl pyrrole (Py)-containing polyamides that can form stacked dim... more N-Methyl imidazole (Im) and N-methyl pyrrole (Py)-containing polyamides that can form stacked dimers can be programmed to target specific DNA sequences in the minor groove of DNA and control gene expression. Polyamides are being investigated as potential medicinal agents for treating diseases including cancer. The naturally occurring polyamide distamycin binds as a dimer in the minor groove of DNA and recognizes sequences rich in A/T and T/A base pairs indiscriminately. Synthetic analogs of distamycin that incorporate N-methylimidazole into the heterocyclic core have been shown to bind to G/C rich sequences with a high degree of specificity. The purpose of this study is to investigate the behavior of polyamides containing the 2,5-linked N-methylpyrrole-2-carboxamide or pyrrole(H) [Py(H)] moiety upon binding to DNA. The synthesis and biophysical characteristics of two polyamides PyPyPyPy(H) 2 and ImPyPyPy(H) 3 designed to test the binding preference of a Py/Pyrrole(H) pairing [Py/Py(H)] and a [Im/Py(H)] is described. Studies utilizing circular dichroism, thermal denaturation (ΔT M), biosensor-surface plasmon resonance and DNase I footprinting show that an [Im/Py(H), 3]
Heterocyclic Communications, 2010
The biophysical and biological evaluations of DNA minor groove binding AT sequence selective benz... more The biophysical and biological evaluations of DNA minor groove binding AT sequence selective benzimidazole analogs of Hoechst 33258 which contain a p-anisyl, a p-[bis(2-chloroethyl)amino]phenyl or a p-anisyl and an amidine moiety are discussed. The preference for all three compounds for the 5 ′-AAATTT-3 ′ sequence was ascertained by thermal denaturation and circular dichroism studies. The mustard-containing compound 4 was found to be more cytotoxic against murine cancer cells grown in culture than the non-mustard containing compound. DNA alkylation was not necessary for anti-Leishmanial activity.
Chemical Biology & Drug Design, 2011
Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyc... more Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyclic ketones were designed, synthesized, and investigated for cytotoxicity against murine B16 and L1210 cancer cell lines. The analogs belong to four structurally divergent series, three of which (series g, h, and i) contain differently substituted cyclopentanone units and the fourth (series j) contains a 3,3-dimethyl-4-piperidinone moiety. Of these, the analogs in series j showed potential cytotoxic activity against murine B16 (melanoma) and L1210 (lymphoma) cells. The most active compounds 5j, 11j, 15j, and 12h produced IC 50 values from 4.4 to 15 lM against both cell lines. A singlecrystal X-ray structure analysis and molecular modeling studies confirmed that these chalcones have an E-geometry about the alkene bond and possess a slightly 'twisted' conformation similar to that of combretastatin A-4. At a concentration of 30 lM, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action.
Biopolymers, 2013
Synthetic N-methyl imidazole and N-pyrrole containing polyamides (PAs) that can form "stacked" di... more Synthetic N-methyl imidazole and N-pyrrole containing polyamides (PAs) that can form "stacked" dimers can be programmed to target and bind to specific DNA sequences and control gene expression. To accomplish this goal, the development of PAs with lower molecular mass which allows for the molecules to rapidly penetrate cells and localize in the nucleus, along with increased water solubility, while maintaining DNA binding sequence specificity and high binding affinity is key. To meet these challenges, six novel f-ImPy*Im PA derivatives that contain different orthogonally positioned moieties were designed to target 5′-ACGCGT-3′. The synthesis and biophysical characterization of six f-ImPy*Im were determined by CD, ΔT M , DNase I footprinting, SPR, and ITC studies, and were compared with those of their parent compound, f-ImPyIm. The results gave evidence for the minor groove binding and selectivity of PAs 1 and 6 for the cognate sequence 5′-ACGCGT-3′, and with strong affinity, K eq = 2.8 × 10 8 M −1 and K eq = 6.2 × 10 7 M −1 , respectively. The six novel PAs presented in this study demonstrated increased water solubility, while maintaining low molecular mass, sequence specificity, and binding affinity, addressing key issues in therapeutic development.
Bioorganic & Medicinal Chemistry Letters, 2013
Bioorganic & Medicinal Chemistry, 2013
Orthogonally positioned diamino/dicationic polyamides (PAs) have good water solubility and enhanc... more Orthogonally positioned diamino/dicationic polyamides (PAs) have good water solubility and enhanced binding affinity, whilst retaining DNA minor groove and sequence specificity compared to their monoamino/monocationic counterparts. The synthesis and DNA binding properties of the following diamino PAs: f-IPI (3a), f-IPP (4), f-PIP (5), and f-PPP (6) are described. P denotes the site where a 1-propylamino group is attached to the N1-position of the heterocycle. Binding of the diamino PAs to DNA was assessed by DNase I footprinting, thermal denaturation, circular dichroism titration, biosensor surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) studies. According to SPR studies, f-IPI (3a) bound more strongly (K eq = 2.4 Â 10 8 M À1) and with comparable sequence selectivity to its cognate sequence 5 0-ACGCGT-3 0 when compared to its monoamino analog f-IPI (1). The binding of f-IPI (3a) to 5 0-ACGCGT-3 0 via the stacked dimer motif was balanced between enthalpy and entropy, and that was quite different from the enthalpy-driven binding of its monoamino parent f-IPI (1). f-IPP (4) also bound more strongly to its cognate sequence 5 0-ATGCAT-3 0 (K eq = 7.4 Â 10 6 M À1) via the side-by-side stacked motif than its monoamino analog f-IPP (2a). Although f-PPP (6) bound via a 1:1 motif, it bound strongly to its cognate sequence 5 0-AAATTT-3 0 (K eq = 4.8 Â 10 7 M À1), 15-times higher than the binding of its monoamino analog f-PPP (2c), albeit f-PPP bound via the stacked motif. Finally, f-PIP (5) bound to its target sequence 5 0-ATCGAT-3 0 as a stacked dimer and it has the lowest affinity among the diamino PAs tested (K eq <1 Â 10 5 M À1). This was about two times lower in affinity than the binding of its monoamino analog f-PIP (2b). The results further demonstrated that the 'core rules' of DNA recognition by monoamino PAs also apply to their diamino analogs. Specifically, PAs that contain a stacked IP core structure bind most strongly (highest binding constants) to their cognate GC doublet, followed by the binding of PAs with a stacked PP structure to two degenerate AT base pairs, and finally the binding of PAs with a PI core to their cognate CG doublet.
Bioorganic & Medicinal Chemistry, 2012
Pyrrole- and imidazole-containing polyamides are widely investigated as DNA sequence selective bi... more Pyrrole- and imidazole-containing polyamides are widely investigated as DNA sequence selective binding agents that have potential use as gene control agents. The key challenges that must be overcome to realize this goal is the development of polyamides with low molar mass so the molecules can readily diffuse into cells and concentrate in the nucleus. In addition, the molecules must have
Bioorganic & Medicinal Chemistry, 2010
The synthesis of an achiral seco-hydroxy-aza-CBI-TMI analog (8) of the duocarmycins is reported. ... more The synthesis of an achiral seco-hydroxy-aza-CBI-TMI analog (8) of the duocarmycins is reported. Its specificity for the DNA minor groove of AT-rich sequences and covalent bonding to adenine-N3 was ascertained by a thermal cleavage assay. Compound 8 was found to be cytotoxic in the nanomolar range against murine and human cancer cells. It was further demonstrated that compound 8 was active against murine melanoma (B16-F0) grown in C57BL/6 mice. Compound 8 was also shown to inhibit the growth of the protozoan parasites Leishmania donovani, Leishmania Mexicana, Trypanosoma brucei, and Plasmodium falciparum in culture.
Biochemistry, 2011
P yrrole (P) and imidazole (I)-containing polyamide analogues of the naturally occurring distamyc... more P yrrole (P) and imidazole (I)-containing polyamide analogues of the naturally occurring distamycin A (1) bind in the minor groove of DNA in a stacked, antiparallel 2:1 (ligand/DNA) motif. 1À3 Early studies have led to the establishment of a set of pairing rules for DNA base pair recognition; a P/P stacking recognizes an A/T or T/A base pair, an I/P stacking binds to a G/C base pair, while a P/I stacking recognizes a C/G base pair. In addition, a stacked I/I pairing targets a T/G mismatch. 4À6 As a result of the high degree of sequence specificity that these molecules exhibit, their potential use as regulators of gene expression has been widely explored. 7 However, attempts to inhibit the transcription of genes that code for a disease in cell lines have been met with moderate success which presumably points toward poor cellular uptake of some of these polyamides and their limited ability to achieve nuclear localization. 8,9 Some success in this area has been achieved through the attachment of
Heterocyclic Communications, 2010
Hairpin polyamide analogs of distamycin A (1) were designed and synthesized to evaluate their abi... more Hairpin polyamide analogs of distamycin A (1) were designed and synthesized to evaluate their ability to bind 5 ′-ATAGA-3 ′ and 5 ′-AGATA-3 ′ sequences which are important elements for controlling the function of the Brn-3b and GATA-3 transcriptional factors, respectively. The hairpin polyamides are composed of pyrrole and imidazole units linked together via a γ-aminobutyrate (GABA) unit. Hairpins 2b (Py-Py-Im-γ-Py-Py-Py) and 2c (Im-Py-Py-γ-Py-Py-Py) were synthesized to target the respective Brn-3b and GATA-3 cognate sequences. Preliminary biophysical studies including thermal denaturation and circular dichroism were performed and the results ascertained the binding of hairpins 2a and 2b to their respective cognate DNA sequences.
Medicinal Chemistry Research, 2011
Eighteen 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs (5a-j, 6a-e, and 7a-c) of combretastatin A... more Eighteen 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs (5a-j, 6a-e, and 7a-c) of combretastatin A-4 were synthesized with the objective of discovering compounds capable of controlling the growth of Trypanosoma lewisii, Leishmania tarantole, Plasmodium falciparum, and Giardia lamblia. Even though the target compounds demonstrated differential cytotoxicity against mammalian cancer cells, with IC 50 values ranging from 0.5 to [100 lM, the range of activity against Trypanosoma, Leishmania, and Plasmodium, and to a good extent for Giardia, was narrow. The IC 50 values of ''active'' compounds against the parasites ranged from about 10 lL to slightly greater than 50 lL. Specifically, compounds 5a, 5g, 5h, 6c, 7a, and 7c were not cytotoxic against mammalian cancer cells (IC 50 [ 100 lM) but showed good activity against the parasites, except Giardia (e.g., compounds 6c and 7a), suggesting that these compounds may act in a similar mechanism in parasites. Compounds 5f and 6b were previously shown to promote microtubule depolymerization in mammalian cells.