Balaji Babu

Chiral Macrocyclic Schiff Bases: An Overview.

Abstract: Macrocyclic Schiff bases form an important class of macrocyclic host systems, which are formed by self condensation of diamine with a diformyl compound. Chiral modification of macrocyclic Schiff bases with different central cavity sizes were recently developed and explored. This mini-review will discuss some of the synthetic strategies, solid state crystal structures, and recent applications of different [n+n] chiral macrocyclic Schiff bases.

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

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.

Hx-amides: DNA sequence recognition by the fluorescent Hx (p-anisylbenzimidazole)•pyrrole and Hx•imidazole pairings

Hx-amides are fluorescent hybrids of imidazole (I)- and pyrrole (P)-containing polyamides and Hoechst 33258, and they bind in the minor groove of specific DNA sequences. Synthesis and DNA binding studies of HxII (5) complete our studies on the first set of Hx-amides: Hx-I/P-I/P. HxPP (2), HxIP (3) and HxPI (4) were reported earlier. Results from DNase I footprinting, biosensor-SPR, CD and ΔTM studies showed that Hx-amides interacted with DNA via the anti-parallel and stacked, side-by-side motif. Hx was found to mimic the DNA recognition properties of two consecutive pyrrole units (PP) in polyamides. Accordingly, the stacked Hx/PP pairing binds preferentially to two consecutive AT base pairs, A/T-A/T; Hx/IP prefers C-A/T; Hx/PI prefers A/T-C; and Hx/II prefers C-C. The results also showed that Hx-amides bound their cognate sequence at a higher affinity than their formamido-triamide counterparts.

Conformational modulation of DNA by polyamide binding: structural effects of f-Im-Py-Im based derivatives on 5′-ACGCGT-3′

The DNA sequence 5′‐ACGCGT‐3′ is in the core site of the Mlu 1 cell‐cycle box, a transcriptional element in the promoter region of human Dbf4 gene that is highly correlated with a large number of aggressive solid cancers. The polyamide formamido‐imidazole‐pyrrole‐imidazole‐amine+ (f‐Im‐Py‐Im‐Am+) can target the minor groove of 5′‐ACGCGT‐3′ as an antiparallel stacked dimer and has shown good activity in inhibiting transcription factor binding. Recently, f‐Im‐Py‐Im‐Am+ derivatives that involve different orthogonally positioned substituents were synthesized to target the same binding site, and some of them have displayed improved binding and pharmacological properties. In this study, the gel electrophoresis–ligation ladders assay was used to evaluate the conformational effects of f‐Im‐Py‐Im‐Am+ and derivatives on the target DNA, an essential factor for establishing the molecular basis of polyamide–DNA complexes and their transcription factor inhibition. The results show that the ACGCGT site in DNA has a relatively wide minor groove and a B‐form like overall structure. After binding with f‐Im‐Py‐Im‐Am+ derivatives, the DNA conformation is changed as indicated by the different mobilities in the gel. These conformational effects on DNA will at least help to point to the mechanism for the observed Mlu 1 inhibition activity of these polyamides. Therefore, modulating DNA transcription by locking the DNA shape or altering the minor groove geometry to affect the binding affinity of certain transcription factors is an attractive possible therapeutic mechanism for polyamides. Some of the substituents are charged with electrostatic interactions with DNA phosphate groups, and their charge effects on DNA gel mobility have been observed. Copyright

Synthesis and DNA-binding Properties of 1,2,3-triazole-linked H-pin Pyrrole- and Imidazole-containing Polyamides Formed by the Huisgen Reaction

Abstract Covalently linked pyrrole (Py)- and imidazole (Im)-containing H-pin polyamides bind in the minor groove of specific DNA sequences with high affinity. The synthesis of 1,2,3-triazole-linked and heterodimeric H-pin polyamides 13a,b formed from the Huisgen reaction of an alkyne-containing f-PyPyPy (6) with an azide-containing f-ImPyIm (7) is reported. The reaction proceeded smoothly under thermal conditions to give an inseparable mixture of 1,4- and 1,5-isomers (13a and 13b, respectively) by column chromatography. When the reaction was conducted under ‘click’ or Cu(I)-catalyzed conditions or in the presence of the cognate DNA sequence, no desired product was observed. Preliminary results from DNA thermal denaturation and circular dichroism titration studies provided evidence of mixture 13a,b binding to the target DNA sequence 5′-TCTCAA-3′.

Design, Synthesis, and Cytotoxicity of Novel 3‐Arylidenones Derived from Alicyclic Ketones

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 IC50 values from 4.4 to 15 μm against both cell lines. A single‐crystal 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 μm, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action.

DNA Recognition: Design, Synthesis and Biophysical Characteristics of Pyrrole(H) Based Polyamides

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] pairing prefers a G/C or C/G pairing whilst a [Py/Py(H), 2] pairing tolerates A/T or T/A base pairs and avoids a G/C base pair.

DNA sequence-selective monoheterocyclic analog of Hoechst 33258: cytotoxicity and antiparasitic properties

Abstract 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.

Synthesis and biophysical studies of hairpin polyamides targeting the Brn-3b and GATA-3 transcriptional sites

Abstract 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.