Diarylureas and Diarylamides with Pyrrolo[2,3-<i>d</i>]pyrimidine Scaffold as Broad-Spectrum Anticancer Agents

Abstract

Cancer is a generic term for a large group of diseases that can affect any part of the body. Lung, stomach, liver, colon, and breast cancer cause the most cancer deaths each year. About 30% of cancer deaths are due to the five leading behavioral and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol intake. More than 70% of all cancer deaths occurred in low-and middle-income countries. Deaths from cancer worldwide are projected to exceed 13 million in 2030.1) In spite of the extensive efforts and investment in research, the management of human malignancies still constitutes a major challenge for contemporary medicinal chemistry. There has been an urgent need for development of more efficient anticancer agents with minimal side effects.Diarylureas and diarylamides have been highlighted as potential antiproliferative agents against a variety of cancer cell lines.2-17) Sorafenib (Nexavar ® , Fig. 1) is an example of anticancer diarylureas that has been approved by the U.S. Food and Drug Administration (FDA) for treatment of advanced renal cancer.18) It has also been approved in Europe for treatment of hepatocellular carcinoma (HCC).19) Sorafenib is currently subjected to clinical trials for other types of cancer. Imatinib (Gleevec ® , Fig. 1) is an example of diarylamides which is used for treatment of chronic myeloid leukemia (CML) with diminished side effects. 20)The target pyrrolo [2,3-d] pyrimidine compounds were designed as conformationally restricted analogs of Sorafenib by isosteric replacement of the 4-phenoxypyridine moiety of the lead compound with a pyrrolo[2,3-d] pyrimidine nucleus (Fig. 1). The 50% inhibitory concentration (IC 50 ) values for most of the target compounds over A375P human melanoma cell line only were previously reported.2,3) Upon further testing over NCI-60 cancer cell line panel of nine different cancer types, the target compounds showed broad-spectrum anticancer activities with high efficacies and potencies. Herein the biological results are reported in details. Results and DiscussionChemistry The target pyrrolo[2,3-d] pyrimidine diarylureas and diarylamides were synthesized by the pathway of reactions illustrated in Charts 2-4.

Escin reduces cell proliferation and induces apoptosis on glioma and lung adenocarcinoma cell lines

“…Cancer incidence has been experiencing a rise in recent years and is still a major health problem in the world (El Gamal and Oh 2014). Moreover, many of the cancers are highly resistant to chemo and radiotherapy, which induce apoptotic cell death pathways (Heinemann 2002;Cao et al 2013).…”

Direct reductive amination of functionalized aldehydes with aniline derivatives of purines and 7-deazapurines

“…According to our working plan, we were interested in applying this procedure to highly functionalized aldehydes incorporating amino and/or ester groups (Scheme 2). As representative aldehydes, we selected N-Boc protected aldehydes where the amino group was either in a chain (6), or in a cycle (7); aldehydes derived from conveniently protected amino acids, such as 8, since amino acids are interesting functionalizing groups in medicinal chemistry; 25 and finally an unsaturated aldehyde with an ethyl ester group (9), so that, under the hydrogenation conditions, the reduction of the double bond would also occur. The results obtained are shown in Scheme 2.…”

“…[1][2][3] Related to them, N-9-arylpurines and, by analogy, 7-phenyl-7H-pyrrolo[2,3-d] pyrimidines 4,5 represent a particularly interesting group of compounds for which different biological studies have been described including antiviral 6 or anticancer activities. 4,[7][8][9] Kinases [10][11][12] and methyl transferases 13,14 are among the most studied targets for these compounds, still their biological applications are in continuous expansion. 15,16 Moreover, the interest on this type of compounds favors the development of efficient methods for their synthesis, as recently reported for the oxidative coupling of purines with N-heterocycles.…”

Pyrrole: A Decisive Scaffold for the Development of Therapeutic Agents and Structure‐Activity Relationship

“…The potency considerably changed when the substitution on the phenyl ring was altered. The efficacy of compound 130 was reduced by a Colon cancer (4.2 � 0.5 μM) [159] 112 Liver cancer (13.4 � 5.8 μM) [159] 113 RD rhabdomyosarcoma cell line (9.0 � 0.7 μM) U-2 OS cell line (19.0 � 0.9 μM) [207] 114 RD rhabdomyosarcoma cell line (8.5 � 0.5 μM) U-2 OS cell line (14.5 � 0.8 μM) SK-LMS-1 leiomyosarcoma (17.0 � 1.4 μM) GISTÀ T1 cell line (15.5 � 1.1 μM) [207] 115 Colon cancer (HT-29) -78 � 2 μM (SW480) -97 � 1 μM [208] Lung cancer (0.36 μM) [209] 118…”