Retinobenzoic acids. 5. Retinoidal activities of compounds having a trimethylsilyl or trimethylgermyl group(s) in human promyelocytic leukemia cells HL-60

Abstract

The retinoidal activities of trimethylsilyl or trimethylgermyl-containing retinobenzoic acids are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. Compounds with a trimethylsilyl or trimethylgermyl group at the meta position of the generic formula 2 have more potent activities than the corresponding retinobenzoic acids with a m-tert-butyl group. Compounds having two m-trimethylsilyl or -trimethylgermyl groups also have strong activities, and (E)-4-[3-[3,5-bis(trimethylsilyl)phenyl]-3-oxo-1-propenyl]benzoic acid (22, Ch55S) and (E)-4-[3-[3,5-bis(trimethylgermyl)phenyl]-3-oxo-1- propenyl]benzoic acid (35, Ch55G) are more active than retinoic acid by 1 order of magnitude. However, in the para-substituted chalcone derivatives, the replacement of a tert-butyl group (49, Ch40) with a trimethylsilyl (27, Ch40S) or a trimethylgermyl (30, Ch40G) group caused the disappearance of the activity.

Synthetic Retinoids: Structure–Activity Relationships

“…The formation of strong hydrogen bonds between synthetic retinoids possessing hydrogen-bond acceptors, such as amide groups in the linker region (e.g., AM 580, [74] AGN 193836 [75] and AM 555S [76] ) and this residue results in RARa selectivity. Selectivity can be further increased by incorporating substituents such as halogens on the hydrophobic group as well as by adding fluorine substituents ortho to the carboxylic acid group (e.g., AGN 193836, which was the first monospecific RARa retinoid to be synthesised).…”

Comparative study of the biological activity of organosilicon and organogermanium compounds

“…However, a practically similar potency of silicon and germanium derivatives (XVc,d) within the concentration interval from 1 to 3nmoldm-3, close to the activity of N-methyl-N-nitrosourea, indicates the possibility of splitting Si-C and Ge-C bonds under experiSome trimethylsilyl and trimethylgermyl derivatives of retinobenzoic acids show high retinoidal activity in human promyelocytic leukaemia cells HL-60. 42 Thus, (E)-4-{3-[3,5-bis(trimethylsilyl)phenyl]-3-0x0-1-propeny1)benzoic acid, XVIb, and its germanium analogue XVIc are one order of magnitude more potent than retinoic acid. Both compounds show activity similar to that of the carbon analogue (Table 7).…”

“…8~ lo-') for a trimethylsilyl or trimethylgermyl group leads to complete loss of activity ( Table 8). 42 It is interesting to note the absolute loss of another activity caused by the same change in the compound structure. Substitution of t-butyl groups by trimethylsilyl or trimethylgermyl in 3 3 -di(t-buty1)-benzaldehyde (XIX) and -acetophenone (XX) both having a musk scent, results in the complete loss of scent, whilst in the case of the corresponding trinitrobenzene derivatives (XXI) this type of substitution increases the musk scent in the silicon derivative and its conservation in the germanium analogue.…”

“…mental biomethylating conditions agent; with this the has formation been confirmed of the same by Me,M-substituted retinobenzoic acid, XXII ( M = C , Si, Ge), with an amide group between the aromatic rings, possesses similar retinoidal activity ( Table 9). 42 SiliconM and germanium45 derivatives of the semicarbazone (XXIII, XXV) and thiosemicarba- (Table lo)). Some of the cyclic silicon and germanium derivatives of cysteamine (XXVI) possess similar or close radioprotective potency (Table 11).…”

Novel Retinoidal Tropolone Derivatives. Bioisosteric Relationship of Tropolone Ring with Benzoic Acid Moiety in Retinoid Structure.

“…The structure at the hydrophobic region or the linking group (X) can be varied with retention of high activity, while the terminal carboxylic acid generally can not be replaced by other functional groups (bioisosters), such as an aminosulfonyl, amidino or tetrazolyl group, without a significant decrease or loss of activity. 6) One exception is the successful replacement of the carboxylic acid of RAR and RXR ligands with a thiazolidinedione moiety. 7) Here, we describe the design, synthesis, and biological activities of tropolone derivatives as novel retinoids without a carboxyl group.…”