Marine natural products from sponges (Porifera) of the order Dictyoceratida (2013 to 2019); a promising source for drug discovery

Marine organisms have been considered an interesting target for the discovery of different classes of secondary natural products with wide-ranging biological activities. Sponges which belong to the order Dictyoceratida are distinctly classified into 5 families: Dysideidae, Irciniidae, Spongiidae, Thorectidae, and Verticilliitidae. In this review, compounds isolated from Dictyoceratida sponges were discussed with their biological potential within the period 2013 to December 2019. Moreover, analysis of the physicochemical properties of these marine natural products was investigated and the results showed that 78% of the compounds have oral bioavailability potential. This review highlights sponges of the order Dictyoceratida as exciting source for discovery of new drug leads.


Introduction
Marine life forms are widely variable, including sponges, corals, ascidians, gorgonians, sea pens, algae, fungi and marine associated micro-organisms which are considered important sources for the discovery of structurally diverse and bioactive secondary metabolites. 1 According to the World Porifera Database, 2 the order Dictyoceratida has been divided into 5 distinct families: Dysideidae, Irciniidae, Spongiidae, Thorectidae, and Verticilliitidae. The family Verticilliitidae has been reclassied recently into this order and contains two genera. Each family possesses its distinctive characteristics such as the ne collagenous laments in the irciniids, the homogeneous skeletal bers of spongiids, the eurypylous choanocyte chambers in dysideids and the opposite of these characteristics in the thorectids (as examples the diplodal choanocyte chambers, pithed and laminated bers and absence of ne laments). 3 There are two reasons which attract us to discuss this order of sponges. The rst reason is the abundant geographical distribution where they were reported from the waters of 31 countries. The major contributors were Korea, Japan, Australia, China, Papua New Guinea and Indonesia. The second reason is the chemical richness and diversity of their metabolites. The order Dictyoceratida (Phylum Porifera, Class Demospongiae, Order Dictyoceratida) has contributed over 20% of new secondary metabolites which were previously derived from all sponges, making it the highest producer among all the sponge orders. In contrast, the orders Haplosclerida, Poecilosclerida, Halichondrida, and Astrophorida contributed with 14.2%, 14%, 10.7% and 9.2%, respectively. The order Lithistida only contributed with 5.5%. 4 Mehbub et al. published a valuable review on the secondary metabolites isolated from the order Dictyoceratida and their biological activities during the period from 2001-2012. 4 This provoked us to establish our review as a part 2 during the period from 2013-2019. The compounds were reported to exhibit different biological activities including cytotoxic, antimicrobial, antiparasitic, anti-H. pylori, antiviral, antioxidant, antiallergic, anti-inammatory, inhibition of atherosclerosis and other activities.
These results agreed with the previous reported review where the major detected two bioactivities exhibited by metabolites were the cytotoxic activity followed by the antimicrobial activity Fig. 1.
In this review, we report all published data regarding secondary metabolites isolated from Dictyoceratida sponges and their biological activities within the period 2013 to Dec 2019 (Table S1 †). In addition, we highlighted the most bioactive compounds with activity less than or equal to 5 mM or 5 mg mL À1 . were isolated from a Hyrtios sp. and showed antimicrobial activity. Also, hyrtioerectines D (1) and F (3) were more active than hyrtioerectine E (2) with 45% and 42% of inhibition in a DPPH free radical scavenging activity test. 5 Another two new alkaloids (4,5) were isolated from the same sponge. Hyrtimomine A (4) showed in vitro cytotoxic activity against human epidermoid carcinoma KB cells and muline leukemia L1210 cells with IC 50 value of 3.1 mg mL À1 and 4.2 mg mL À1 , respectively. 6 Hyrtimomines A (4) and B (5) showed antimicrobial activities against Candida albicans (IC 50 : 1.0 mg mL À1 , each) and C. neoformans (IC 50 : 2.0 and 4.0 mg mL À1 , respectively). Also, hyrtimomine A (4) exhibited an antifungal activity against Aspergillus niger (IC 50 : 4.0 mg mL À1 ). 7 Hyrtimomine D (6), a bisindole alkaloid from Hyrtios sp. was reported to exhibit an inhibitory activity against C. albicans and Cryptococcus neoformans (IC 50 : 4 mg mL À1 ) and showed inhibitory activity against Staphylococcus aureus with MIC value of 4 mg mL À1 . 6 Hyrtimomine I (7) showed antifungal effect against C. neoformans (IC 50 : 4.0 mg mL À1 ). 7 A new scalarane sesterterpene, the hemiacetal of 12-deacetylcis-24a,25a-dimethoxyscalarin (8) from Hyrtios sp. showed inhibition of TDP-43 binding to its DNA target strand and stimulated its cytoplasmic translocation and its tendency to aggregate. This could be considered as a chemical exploration in the study of the TDP-43 aggregation state and its cellular localization. 8 Nakijinol G (9), a new meroterpenoid from Hyrtios sp. was evaluated for its protein tyrosine phosphatase (PTP1B) inhibitory and cytotoxic activities. Results showed a signicant PTP1B inhibition with an IC 50 value of 4.8 mM, where no cytotoxicity against four human cancer cell lines was detected. 9 From the sponge H. communis, thorectidaeolide A (10) and 4acetoxythorectidaeolide A (11), two new sesterterpenes were isolated and reported to be highly potent inhibitors of hypoxia (1% O 2 )-induced HIF-1 activation with IC 50 values of 3.2 and 3.5 mM, respectively. 10  A new mero sesquiterpene, 19-methoxy-9,15-ene-puupehenol (13) was active at 1.78 mM on scavenger receptor-Class B type 1 HepG2 (SR-B1 HepG2) stable cell lines. So, it can be considered a target for treating atherosclerosis disease. 12 Petrosaspongiolactam A (14), a new sesterterpene lactam isolated from Petrosaspongia sp. was reported to inhibit of TDP-43 binding tendency to its DNA target strand and was more active than petrosaspongiolactam B. 8 From the sponge Smenospongia aurea, smenamides A (15) and B (16) were isolated and showed potent cytotoxic activity at nanomolar concentrations against lung cancer Calu-1 cells, where compound (15) exerted its activity through a clear proapoptotic mechanism. The IC 50 values for smenamides A and B were 8 nM and 49 nM, respectively. This makes smenamides promising leads for antitumor drug design. 13 Toward the synthesis of smenamide A (15), a study reported the synthesis of two stereoisomers named ent-smenamide A and 16-epi-smenamide. This study also established the previously unknown relative and absolute congurations of smenamide A (15). 14 Another study discussed the synthesis of 16-epi-analogue of smenamide A and eight analogues in the 16-epi series to determine the role of the structure activity relationship features. The synthetic analogues were tested on multiple myeloma (MM) cell lines and the results showed that the conguration at C-16 slightly affects the activity, since the 16-epi-smenamide A was still active at nanomolar concentrations. Interestingly, it has been found that the analogue which contains the pyrrolinone terminus, was inactive while the analogue which composed of the intact C12-C27 portion, retained its activity, even though its EC 50 value was 1000 times smaller compared with the parent 16- epi-smenamide A. In addition, this analogue was found to be able to block the cell cycle at the G 0 /G 1 phase. 15 Also from the same species (S. aurea), smenothiazoles A (17) & B (18) were isolated and showed potent cytotoxic activity at nanomolar concentrations on four different cell lines (Calu-1 and LC31 lung-cancer cells, A2780 ovarian cancer cells and MCF7 breast cancer cells). The tumor cells were treated for 48 h with different concentrations of the two compounds. Aer this time, the cells appeared elongated and attened under the optical microscope. Also, some cells showed small vacuoles in their cytoplasm. All this indicated cell death. These morphological changes were observed at concentrations $50 nM. Moreover, at 100 nM, all cells in the suspension were dead. In contrast, the morphology of treated cells was similar to that of untreated cells at concentrations of 1, 10 and 30 nM. 16 Later in 2017, smenothiazole A (17) was isolated from the sponge Consortium plakortis symbiotica-Xestospongia deweerdtae. The anti-tuberculosis activity of smenothiazole A (17) was in vitro evaluated against Mycobacterium tuberculosis H37Rv and the results showed that smenothiazole A (17) exhibited signicant activity with MIC value of 4.1 mg mL À1 . Synthesis and subsequent biological screening of a dechlorinated analogue of smenothiazole A, revealed that the chlorine atom is necessary for the anti-TB activity. 17 Also in 2017, total synthesis of smenothiazole A (17) was reported. In this reaction, silastannation, Stille reaction and carefully controlled desilylchlorination were This journal is © The Royal Society of Chemistry 2020 RSC Adv., 2020, 10, 34959-34976 | 34961 appointed as key steps to construct the unique polyketide acid fragments. The optimized reaction conditions avoided the migration of 2,5-diene to a 2,4-conjugated system. 18 A new sesquiterpene (+)-5-epi-20-O-ethylsmenoquinone (19) was reported from S. aurea and S. cerebriformis. This compound exhibited inhibition tumor growth at 0.75 and 1.5 mM against   concentrations. 20 From S. cerebriformis, a new naphtoquinone smenocerone B (23) was reported and signicantly exhibited cytotoxic activity against hepatocellular carcinoma (HepG-2), promyelocytic leukemia (HL-60) and breast carcinoma (MCF-7) human cancer cells with IC 50 values of 3.2 AE 0.2, 4.0 AE 0.7 and 4.1 AE 0.8 mg mL À1 , respectively. 21 From the marine sponge Scalarispongia sp., four new scalarane sesterterpenoids were isolated. Cytotoxicity was evaluated against six human cancer cell lines and only compound (24) exhibited a signicant cytotoxicity against breast (MDA-MB-231) cell line with (GI 50 values down to 5.2 mM). 22 Zampanolides B and C (25,26) are new macrolides which were isolated from Cacospongia mycojiensis. They were found to have a potent nanomolar cytotoxic effect toward the HL-60 cell line with IC 50 of 3.3 and 3.8 nM, respectively 23 Fig. 3.

Potent bioactive compounds isolated from family Spongiidae
Reviewing published data within 2013-2019 revealed that 70 new and 36 known compounds were reported from the family Spongiidae. The new sesquiterpene quinone, 20-demethoxy-20methylaminodactyloquinone D (73), that was isolated from Spongia pertusa Esper; showed CDK-2 affinity with a K d value of 4.8 mM. It was considered as the rst example of a sesquiterpene quinone derived from a marine source with CDK-2 affinity which requires further functional investigations on CDK-2. 43 From Hippospongia sp., a new sesterterpene named hippospongide C (74) was isolated. Cytotoxic activity was evaluated against different cell lines and the results showed that hippospongide C exhibited a signicant cytotoxic activity against T-47D and K562 cell lines with IC 50 values of 4.1 and 2.9 mg mL À1 , respectively. 44 Hippolachnin A (75), a polyketide with an unprecedented carbon skeleton of a four-membered ring, was isolated from the South China Sea sponge H. lachne. It was reported that hippolachnin A exhibited potent antifungal activity against three different pathogenic fungi, Cryptococcus neoformans, Trichophyton rubrum, and Microsporum gypseum, with a MIC value of 0.41 mM for each fungus. 45 Later in 2017, synthetic method of (AE)-hippolachnin A was reported. 46 Also, a diversiable and scalable synthesis of (AE)-hippolachnin A was denitely described according to Thiocarbonyl Ylide Chemistry. 47 In 2018, synthesis of hippolachnin A was reported taking into consideration structure-activity relationship studies. This study revealed that, in contrast to initial studies, hippolachnin A and several structural analogues lack activity against pathogenic fungi. 48 Also, a unied strategy was reported for divergent synthesis of different types of polyketides. This strategy enabled total synthesis of the enantioselective form of (+)-hippolachnin A based on a series of bio-inspired, rationally designed transformations. 49 In 2019, synthesis of the racemic (AE)-hippolachnin, which serves as a platform for the synthesis of bioactive analogues was reported. Biological testing of this synthetic material did not conrm the previously reported antifungal activity of hippolachnin A but resulted in a moderate activity against nematodes and microbes. 50 Also, from H. lachne, a pair of enantiomeric sesterterpenoids, (À) & (+) hippolide J (76 and 77), were isolated. The evaluation of the antifungal activity of (À) and (+) enantiomers revealed that both showed potent antifungal activity against three strains of hospital-acquired pathogenic fungi, namely, C. albicans SC5314, C. glabrata 537, and Trichophyton rubrum Cmccla, with IC 50 values of 0.125-0.25 mg mL À1 . 51 From Coscinoderma sp., six new sesterterpenes (78) and coscinolactam C-G (79-83) classied as suvanines were isolated. All suvanines exhibited signicant cytotoxic activities against the K562 cell line with IC 50

Potent bioactive compounds isolated from family Irciniidae
New and known compounds which were isolated within 2013-2019 from the family Irciniidae are nearly equal (35 and 32, respectively). A new 9,11-secosterol (84) with the 2-ene-1,4-dione moiety was isolated from the marine sponge Ircinia sp. and this compound was evaluated for its antibacterial activity against different bacterial strains. The most signicant activity was detected against Micrococcus lutes ATCC 9341 with the IC 50 value of 3.1 mg mL À1 . 53 From the sponge Ircinia felix, a new 24homoscalarane sesterterpenoid, felixin F (85) was isolated. The cytotoxicity of felixin F against the proliferation of a limited type of tumor cell lines was evaluated and the results showed modest cytotoxicity towards the leukemia K562, MOLT-4, and SUP-T1 cell lines with IC 50 values of 1.27, 2.59 and 3.56 mM, respectively. 54 Three new furanosesterterpene tetronic acids, sulawesins A-C (86-88), were isolated from a Psammocinia sp. marine sponge. These isolated compounds were proved to inhibit the deubiquitinating enzyme USP7, which could be considered as an emergent target of cancer therapy, with IC 50 values in the range of 2.7-4.6 mM (ref. 55) Fig. 9.
It is noteworthy that no available researches were traced concerning the h family (Verticilliitidae) of this order. Additionally, several compounds were produced as artifacts (89-100) through intended reaction or unintended procedures.
Two derivatives a-16-methoxyfuroscalarol and b-16-methoxyfuroscalarol (89, 90) were obtained through the unintended chemical transformation of furoscalarol which was isolated from Scalarispongia sp. It could be postulated that the slightly acidic character of silica easily induced the formation of an oxocarbenium, which was followed by nucleophilic conjugate Fig. 9 Structures of compounds (84-88).
This journal is © The Royal Society of Chemistry 2020 RSC Adv., 2020, 10, 34959-34976 | 34969 addition of methanol. The formation of an a-product (89) was likely favored because of the approach of the nucleophile toward the pseudoaxial direction for maximum overlap with the p-orbital. 56 Another three sesquiterpenes (91-93) were isolated as solvent-generated artifacts from Spongia pertusa Esper because the extraction was processed with ethanol as a solvent. 43 On the other hand, four ester derivatives [acetyl (94), butyryl (95), hexanoyl (96), and benzoyl (97)] were prepared from 2-(30,50-dibromo-20-methoxyphenoxy)-3,5-dibromophenol and their activities were evaluated against PTP1B and two cancer cell lines in order to investigate the structure-activity relationship features. Although compounds 94-97 exhibited potent inhibitory activities against PTP1B with IC 50 range of (0.62-0.97 mM), cytotoxicity against HCT-15 and Jurkat cells was observed as a similar efficacy to that of the parent compound. 57 Concerning Fascaplysinopsis sp., three new cytotoxic sponge derived nitrogenous macrolides salarin A (98), salarin C (99) Fig. 10 Structures of compounds (89-100). and tulearin A (100), were prepared and evaluated as inhibitors of K562 leukemia cells. A preliminary structure-activity relationship studies revealed that the most sensitive functional groups were the 16,17-vinyl epoxide in both salarins, the triacylamino group in salarin A and the oxazole in salarin C (less sensitive). Regioselectivity of reactions was also found for tulearin A 58 Fig. 10.
Later in 2015, salarin C was evaluated for its activity against chronic myeloid leukemia (CML) cells, especially aer their incubation in atmosphere at 0.1% oxygen. Salarin C induced mitotic cycle arrest, apoptosis and DNA damage. It also concentration-dependently inhibited the maintenance of stem cell potential in cultures in low oxygen of either CML cell lines   This journal is © The Royal Society of Chemistry 2020 RSC Adv., 2020, 10, 34959-34976 | 34971 or primary cells. 59 In 2017, the synthesis of the eastern section of salarin C was reported employing a halogen dance reaction to assemble the trisubstituted oxazole moiety. The synthesis was inspired according to Kashman's hypothesis on the biomimetic oxidation of salarin C to salarin A. 60 In 2018, a study toward the total synthesis of salarin C was reported. This strategy based on the synthesis of dideoxysalarin C as a potential intermediate for the total synthesis of the marine macrolide salarin C. The macrolactone core of dideoxysalarin C was assembled by Suzuki coupling between alkyl iodide and vinyl iodide and Shiina macrolactonization as key steps in the total synthesis. All macrocyclic intermediates during the synthesis were found to be of limited stability. 61 Also, the synthesis of the macrocyclic core of salarin C was described using two epoxides being replaced by alkene moieties. In the key step, ring-closing metathesis exclusively afforded the (E)-product. Additionally, the trisubstituted oxazole unit embedded in the 17-membered ring underwent photo-oxidation on treatment with singlet oxygen, giving macrocyclic trisacylamines. 62 Concerning tulearin A, according to ref. 63 an application to the total synthesis of tulearin A was reported. This application depended on the reaction of lactones with the reagent generated in situ from CCl4 and PPh3 in a Wittig-type fashion to give gemdichloro-olen derivatives. Such compounds can undergo reductive alkylation on treatment with organolithium reagents RLi to furnish acetylene derivatives. The reaction can be enhanced with either Cu(acac) 2 or Fe(acac) 3 /1,2-diaminobenzene. Additionally, two alkynol derivatives were prepared using this way from readily accessible lactone precursors served as the key transformation steps for the total synthesis of the cytotoxic marine derived macrolides tulearin A and C Fig. 10.

Analysis of drug-like physicochemical properties
A necessary requirement for a drug is acceptable aqueous solubility and intestinal permeability. These properties are   necessary but do not discriminate drugs from non-drugs. 64 By calculating the physico-chemical properties, it is possible to predict the oral bioavailability of each compound. Lipinski's rule of 5 (Ro5) considers orally active compounds and denes four simple physico-chemical parameter ranges (molecular weight # 500, log P # 5, hydrogen bond donor # 5, hydrogen bond acceptor # 10) associated with 90% of orally active drugs that have achieved phase II clinical status. If a compound fails the Ro5, there is a high probability that oral activity problems will be encountered. However, passing the Ro5 is no guarantee that a compound is drug-like. Topological polar surface area (tPSA) is an additional descriptor that has been shown to correlate with passive molecular transport through membranes, and therefore allows prediction of transport properties of drugs. It was shown that PSA # 140Å and number of rotatable bonds The log P histogram of the 100 MNP followed a normal distribution with the maximum around 4-6 and 58% of the compounds had a favorable log P value less than 5 Fig. 11B. Notably, compounds with large molecular weights were also found to show high log P values, such as sulawesin C with MW 819 and log P 11.06. Surprisingly, regarding to calculated HBA and HBD, all of 100 compounds introduced in this review were within the Lipinski-compliant region. The distribution of HBD Fig. 11C and HBA Fig. 11D showed a similar pattern. Overall, 45 of the 100 compounds did not violate Lipinski's rule of ve, and 88 compounds had one violation or less. Around 78% of the compounds showed favorable oral bioavailability properties Fig. 11E.

Conclusion
Marine sponges and other marine lifes form have a very important role in drug discovery due to the diverse range of bioactive compounds which are isolated from different environmental and geographic conditions. The order Dictyoceratida (Phylum Porifera, Class Demospongiae, Order Dictyoceratida) consists of ve families Thorectidae, Dysideidae, Spongiidae, Irciniidae and Verticilliitidae. Several diverse classes of secondary metabolites were reported within 2013-2019 period. Terpenes were the major reported chemical class consisting of 73% including simple terpenes, diterpenes, sesquiterpenes, sesterterpenes and other terpenes. The second major class was nitrogenous compounds consisting of 13% including alkaloids, alkaloids related and other nitrogenous compounds Fig. 12. These different classes can be summarized as 54% new isolated compounds compared to 44% known compounds Fig. 13.
Reviewing the published data and following the number of isolated compounds per year, Fig. 14 and 15 showed that 149 compounds were isolated in 2018 and published in 20 scientic papers whereas 136 compounds were isolated in 2017 and published in 29 papers.
Analysis of the physicochemical properties of these 100 MNPs showed that 45 of the 100 compounds did not violate Lipinski's rule of ve, and 88 compounds had one violation or less. The majority of compounds (72%) are distributed between 300 Da and 500 Da and 58% of the compounds had a favorable log P value less than 5. Interestingly, 78% of the compounds have favorable oral bioavailability properties for different biological activities which are demonstrated in Fig. 16. The majority of orally bioavailable compounds were reported to have cytotoxic, antitumor or anti-proliferative activities. The second major activity was the antimicrobial one. The increasing number of isolated bioactive compounds can provoke researchers for more investigations and studies of sponges belonging to the order Dictyoceratida.

Conflicts of interest
There are no conicts to declare.