Rifamycins are a group of macrocyclic
antibiotics mainly used for
the treatment of various bacterial infections including tuberculosis.
Spectroscopic studies of rifamycins evidence the formation of temperature-
and solvent-dependent equilibria between A-, B-, and C-type conformers
in solutions. The B- and C-type conformers of rifamycin antibiotics
are exclusively formed in the presence of water molecules. A- and
B-type conformers exhibit a hydrophilic and “open” ansa-bridge nature whereas the C-type conformer is more
lipophilic due to the presence of a “closed” ansa-bridge structure. The involvement of the lactam moiety
of the ansa-bridge in intramolecular H-bonds within
rifapentine and rifampicin implicates the formation of a more hydrophilic
A-type conformer. In contrast to rifampicin and rifapentine, for rifabutin
and rifaximin, the “free” lactam group enhances conformational
flexibility of the ansa-bridge, thereby enabling
interconversion between A- and C-type conformers. In turn, an equilibrium
between A- and C-type conformers for rifamycins improves their adaptation
to the changing nature of bacteria cell membranes, especially those
of Gram-negative strains and/or to efflux pump systems.
Geldanamycin (
GDM
) has been modified by different type neutral/acidic/basic substituents (
1
–
7
) and by quinuclidine motif (
8
), transformed into ammonium salts (
9
–
13
) at C(17). These compounds have been characterised by spectroscopic and x-ray methods. Derivative
8
shows better potency than
GDM
in MCF-7, MDA-MB-231, A549 and HeLa (IC
50
s = 0.09–1.06 µM). Transformation of
8
into salts
9
–
13
reduces toxicity (by 11-fold) at attractive potency, e.g. MCF-7 cell line (IC
50
∼2 µM). Our studies show that higher water solubility contributes to lower toxicity of salts than
GDM
in healthy CCD39Lu and HDF cells. The use of
13
mixtures with potentiators PEI and DOX enhanced anticancer effects from IC
50
∼2 µM to IC
50
∼0.5 µM in SKBR-3, SKOV-3, and PC-3 cancer cells, relative to
13
. Docking studies showed that complexes between quinuclidine-bearing
8
–
13
and Hsp90 are stabilised by extra hydrophobic interactions between the C(17)-arms and K58 or Y61 of Hsp90.
Origin, division, and key structural aspects for biological functionality of ansamycins are discussed. Semisynthetic, mutasynthetic and hybrid approaches, yielding new macrolactams, along their mechanism of action and biological potency are compared.
This report concerns biosyntheses, structural division and mechanism of biological potency in view of conformation and zwitterionization of naphthalenoid ansamycins. These macrolactams are discussed especially in view of antibacterial effects.
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