Synthesis and Cytotoxicity Studies of New (Dimethylamino)‐Functionalised and 7‐Azaindole‐Substituted ‘Titanocene’ Anticancer Agents (7‐Azaindole=1H‐Pyrrolo[2,3‐b]pyridine)

Abstract

From the carbolithiation of 1-(cyclopenta-2,4-dien-1-ylidene)-N,N-dimethylmethanamine (¼ 6-(dimethylamino)fulvene; 3) and different lithiated azaindoles 2 (1-methyl-7-azaindol-2-yl, 1-[(diethylamino)methyl]-7-azaindol-2-yl, and 1-(methoxymethyl)-7-azaindol-2-yl), the corresponding lithium cyclopentadienide intermediates 4a -4c were formed (7-azaindole ¼ 1H-pyrrolo[2,3-b]pyridine). The latter underwent a transmetallation reaction with TiCl 4 resulting in the (dimethylamino)-functionalised titanocenes 5a -5c. When the titanocenes 5a -5c were tested against LLC-PK cells, the IC 50 values obtained were of 8.8, 12, and 87 mm, respectively. The most cytotoxic titanocene, 5a, with an IC 50 value of 8.8 mm is nearly as cytotoxic as cis-platin, which showed an IC 50 value of 3.3 mm when tested on the epithelial pig kidney LLC-PK cell line, and ca. 200 times better than titanocene dichloride itself.Introduction. -Titanium-based reagents have significant potential activity against solid tumors. Budotitane (¼ cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium(IV)) looked very promising during its preclinical evaluation but did not go beyond phase-I clinical trials, although a Cremophor EL based formulation was found for this rapidly hydrolyzing molecule [18 -20] allow direct access to highly substituted titanocenes via reductive dimerisation, carbolithiation, or hydridolithiation of the fulvene followed by transmetallation in the last two cases.Titanocene Y (¼ dichloridobis{ (1,2,3,4,5-h)-1-[(4-methoxyphenyl)methyl]cyclopenta-2,4-dien-1-yl}titanium), which has an IC 50 value of 21 mm when tested on the LLC-PK cell line, was synthesised through hydridolithiation of 6-(p-anisyl)fulvene and Superhydride (Li[BEt 3 H]) followed by transmetallation with TiCl 4 [12]. The antiproliferative activity of titanocene Y has been studied in 36 human tumor cell lines [21] and in explanted human tumors [22]. These in vitro and ex vivo experiments showed that prostate, cervix, and renal cell cancer are prime targets for these novel classes of titanocenes, whereas the IC 50 values for the breast-cancer cell lines were very

Advances in Carbolithiation

“…For example, carbolithiation of 6-(dimethylamino)fulvene 46 at low temperature generates cyclopentyllithium species 47, which can be trapped by titanium tetrachloride, forming the corresponding functionalized titanocene complexes 48 that were isolated in moderate to good yields (Scheme 11.14) [24][25][26].…”

“…Notably, this carbolithiation reaction allows for a straightforward synthesis of a library of such titanocene complexes possessing cytotoxic activity and currently being investigated as efficient anticancer agents [24][25][26].…”

Reaction of Arylnitroso Derivatives: Synthesis of Arylimino 2,5-Dihydrofuran and Arylamino Fulvenes Derivatives

“…These structures are subunit of several bioactive natural and synthetic products [14] [15]. Fulvenes have high relevance as synthons [16] [17] and materials [18]- [24]. This report will provide a fast and easy protocol to execute the preparation of the abovementioned heterocycles cores.…”

Synthesis and evaluation of biological activities of new sulfonamide and carbamate derivatives of 1H-pyrrolo[2,3-b]pyridine (7-azaindole)

“…They have attracted considerable interest from the chemical community because of their potential applications in natural product synthesis and pharmaceuticals due to their hydrogen bonding properties and excellent water solubility. The 1H-pyrrolo [2,3-b]pyridine moiety exhibits a broad spectrum of biological activities, including anticancer [2], antitumor [3][4][5], anti-angiogenic [6], antimicrobial [7], as inhibitor of HIV-1 [8,9] and cell division cycle of 7-kinase [10], antifungal [11], analgesic [12], antimalarial [13], antiproliferative [14,15], antibacterial [16], reducing chronic pain [17], as cisplatin and transplatin derivatives [18], antimycobacterial [19], as Topoisomerase I inhibitors [20] and protein kinase inhibition [21], etc. Azaindole and its core containing compounds which include neocryptolepine (1), variolin-B (VAR-B) (2) and grossularines (3) are natural products, while 7-aza-rebeccamycin (4) and 5-azaellipticine (5) are of synthetic origin, whose activity is related to DNA, i.e.…”